NZ725780B2 - Method for selecting personalized tri-therapy for cancer treatment - Google Patents
Method for selecting personalized tri-therapy for cancer treatment Download PDFInfo
- Publication number
- NZ725780B2 NZ725780B2 NZ725780A NZ72578015A NZ725780B2 NZ 725780 B2 NZ725780 B2 NZ 725780B2 NZ 725780 A NZ725780 A NZ 725780A NZ 72578015 A NZ72578015 A NZ 72578015A NZ 725780 B2 NZ725780 B2 NZ 725780B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- hsa
- mir
- intervention
- genes
- points
- Prior art date
Links
- 201000011510 cancer Diseases 0.000 title claims abstract description 43
- 238000002560 therapeutic procedure Methods 0.000 title description 16
- 239000003814 drug Substances 0.000 claims abstract description 82
- 229940079593 drugs Drugs 0.000 claims abstract description 73
- 229920001239 microRNA Polymers 0.000 claims description 84
- 239000002679 microRNA Substances 0.000 claims description 77
- 108020004388 MicroRNAs Proteins 0.000 claims description 76
- 206010028980 Neoplasm Diseases 0.000 claims description 74
- 108020004999 Messenger RNA Proteins 0.000 claims description 70
- 229920002106 messenger RNA Polymers 0.000 claims description 70
- 230000035772 mutation Effects 0.000 claims description 63
- 230000014509 gene expression Effects 0.000 claims description 58
- 230000037361 pathway Effects 0.000 claims description 44
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 39
- 229920003013 deoxyribonucleic acid Polymers 0.000 claims description 36
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 claims description 23
- 108040005185 1-phosphatidylinositol-3-kinase activity proteins Proteins 0.000 claims description 23
- 230000003213 activating Effects 0.000 claims description 21
- 102000003964 Histone deacetylases Human genes 0.000 claims description 19
- 108090000353 Histone deacetylases Proteins 0.000 claims description 19
- 102100013322 MTOR Human genes 0.000 claims description 19
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 claims description 18
- 230000033115 angiogenesis Effects 0.000 claims description 15
- -1 Immune Modulators Proteins 0.000 claims description 14
- 230000000051 modifying Effects 0.000 claims description 14
- 230000004913 activation Effects 0.000 claims description 13
- 230000034659 glycolysis Effects 0.000 claims description 13
- 108010009906 Angiopoietins Proteins 0.000 claims description 11
- 102000009840 Angiopoietins Human genes 0.000 claims description 11
- 240000001340 Gmelina philippensis Species 0.000 claims description 11
- 230000006909 anti-apoptosis Effects 0.000 claims description 11
- 230000002424 anti-apoptotic Effects 0.000 claims description 11
- 230000033616 DNA repair Effects 0.000 claims description 10
- 108050005080 Notch Proteins 0.000 claims description 10
- 102000014736 Notch Human genes 0.000 claims description 10
- 108010017842 Telomerase Proteins 0.000 claims description 10
- 102000004591 Telomerase Human genes 0.000 claims description 10
- 102100019730 TP53 Human genes 0.000 claims description 9
- 238000010192 crystallographic characterization Methods 0.000 claims description 9
- 102100002050 ROS1 Human genes 0.000 claims description 7
- 101710027587 ROS1 Proteins 0.000 claims description 7
- 101710026335 TP53 Proteins 0.000 claims description 7
- 101700054115 ROS1A Proteins 0.000 claims description 6
- 229940035295 Ting Drugs 0.000 claims description 6
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 claims 5
- 239000000203 mixture Substances 0.000 description 78
- 239000003112 inhibitor Substances 0.000 description 55
- 230000002401 inhibitory effect Effects 0.000 description 54
- 102000018233 Fibroblast growth factor family Human genes 0.000 description 39
- 108050007372 Fibroblast growth factor family Proteins 0.000 description 39
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 39
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 39
- 101700007719 RAF1 Proteins 0.000 description 39
- 108020004532 RAS Proteins 0.000 description 35
- 101700069422 ZHX2 Proteins 0.000 description 35
- 102100007290 CD274 Human genes 0.000 description 34
- 101710012053 CD274 Proteins 0.000 description 34
- 102100016115 RAF1 Human genes 0.000 description 33
- 101700064281 ATP1 Proteins 0.000 description 32
- 102100005310 CTLA4 Human genes 0.000 description 30
- 101700054183 CTLA4 Proteins 0.000 description 30
- 102100016823 MAPK1 Human genes 0.000 description 29
- 101700083887 MAPK1 Proteins 0.000 description 28
- 102000013814 Wnt Human genes 0.000 description 26
- 108050003627 Wnt Proteins 0.000 description 26
- 108090000430 Phosphatidylinositol 3-Kinases Proteins 0.000 description 21
- 102000003993 Phosphatidylinositol 3-Kinases Human genes 0.000 description 21
- 210000001519 tissues Anatomy 0.000 description 20
- 102100014231 IGF1 Human genes 0.000 description 19
- 101700074337 IGF1 Proteins 0.000 description 19
- 101700040665 IGF Proteins 0.000 description 18
- 101710043860 ANGPT1 Proteins 0.000 description 17
- 102000004000 Aurora Kinase A Human genes 0.000 description 17
- 108090000461 Aurora Kinase A Proteins 0.000 description 17
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 17
- CYOHGALHFOKKQC-UHFFFAOYSA-N Selumetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1Cl CYOHGALHFOKKQC-UHFFFAOYSA-N 0.000 description 16
- 208000002154 Non-Small-Cell Lung Carcinoma Diseases 0.000 description 15
- 108009000071 Non-small cell lung cancer Proteins 0.000 description 15
- 229950010746 Selumetinib Drugs 0.000 description 15
- 229950007217 Tremelimumab Drugs 0.000 description 15
- 239000000523 sample Substances 0.000 description 15
- 108010072993 tremelimumab Proteins 0.000 description 15
- VWMJHAFYPMOMGF-ZCFIWIBFSA-N 2-[(1R)-1-[(6-amino-5-chloropyrimidine-4-carbonyl)amino]ethyl]-N-[5-chloro-4-(trifluoromethyl)pyridin-2-yl]-1,3-thiazole-5-carboxamide Chemical compound N([C@H](C)C=1SC(=CN=1)C(=O)NC=1N=CC(Cl)=C(C=1)C(F)(F)F)C(=O)C1=NC=NC(N)=C1Cl VWMJHAFYPMOMGF-ZCFIWIBFSA-N 0.000 description 14
- 238000004458 analytical method Methods 0.000 description 13
- 108020001180 rasD Proteins 0.000 description 11
- 230000003321 amplification Effects 0.000 description 10
- 102000017256 epidermal growth factor-activated receptor activity proteins Human genes 0.000 description 10
- 108040009258 epidermal growth factor-activated receptor activity proteins Proteins 0.000 description 10
- 101710007041 let-363 Proteins 0.000 description 10
- 102100011141 ALK Human genes 0.000 description 9
- OROGSEYTTFOCAN-DNJOTXNNSA-N Codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 9
- 229920000665 Exon Polymers 0.000 description 9
- 101710033922 KRAS Proteins 0.000 description 9
- 206010027476 Metastasis Diseases 0.000 description 9
- 102100019764 PDCD1 Human genes 0.000 description 9
- 229960003005 axitinib Drugs 0.000 description 9
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 9
- 238000004364 calculation method Methods 0.000 description 9
- 238000003199 nucleic acid amplification method Methods 0.000 description 9
- 102100004328 BRAF Human genes 0.000 description 8
- 101700004551 BRAF Proteins 0.000 description 8
- 229950003968 Motesanib Drugs 0.000 description 8
- RAHBGWKEPAQNFF-UHFFFAOYSA-N Motesanib Chemical compound C=1C=C2C(C)(C)CNC2=CC=1NC(=O)C1=CC=CN=C1NCC1=CC=NC=C1 RAHBGWKEPAQNFF-UHFFFAOYSA-N 0.000 description 8
- 108060007796 SPATA2 Proteins 0.000 description 8
- 238000003780 insertion Methods 0.000 description 8
- KTEIFNKAUNYNJU-GFCCVEGCSA-N Crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 7
- 102100009279 KRAS Human genes 0.000 description 7
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 7
- 206010061289 Metastatic neoplasm Diseases 0.000 description 7
- 102100008799 PTEN Human genes 0.000 description 7
- 102100006051 RET Human genes 0.000 description 7
- 229960005061 crizotinib Drugs 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000010195 expression analysis Methods 0.000 description 7
- 238000002626 targeted therapy Methods 0.000 description 7
- 102100013180 KDR Human genes 0.000 description 6
- 102200006531 KRAS G12V Human genes 0.000 description 6
- MTCFGRXMJLQNBG-REOHCLBHSA-N L-serine Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 6
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 6
- 102100007893 PRKCA Human genes 0.000 description 6
- 101710038828 PRKCA Proteins 0.000 description 6
- 229960004390 Palbociclib Drugs 0.000 description 6
- AHJRHEGDXFFMBM-UHFFFAOYSA-N Palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 6
- 108060008444 TPR Proteins 0.000 description 6
- 230000000875 corresponding Effects 0.000 description 6
- 239000003596 drug target Substances 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- 101710030209 lin-45 Proteins 0.000 description 6
- 201000005202 lung cancer Diseases 0.000 description 6
- 230000001225 therapeutic Effects 0.000 description 6
- 229920000160 (ribonucleotides)n+m Polymers 0.000 description 5
- 102100001248 AKT1 Human genes 0.000 description 5
- 101700006234 AKT1 Proteins 0.000 description 5
- 102100007281 BRCA1 Human genes 0.000 description 5
- 102100019398 CDK4 Human genes 0.000 description 5
- 101700008359 CDK4 Proteins 0.000 description 5
- 102100001119 NRAS Human genes 0.000 description 5
- 101710033916 NRAS Proteins 0.000 description 5
- 102100016979 PRKCB Human genes 0.000 description 5
- 101710038830 PRKCB Proteins 0.000 description 5
- 102100008209 TSC1 Human genes 0.000 description 5
- 238000001574 biopsy Methods 0.000 description 5
- 210000004027 cells Anatomy 0.000 description 5
- 238000009396 hybridization Methods 0.000 description 5
- 238000002493 microarray Methods 0.000 description 5
- 210000004877 mucosa Anatomy 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 230000001105 regulatory Effects 0.000 description 5
- 108060007281 scc-3 Proteins 0.000 description 5
- 230000004083 survival Effects 0.000 description 5
- 102100000648 ATM Human genes 0.000 description 4
- 108060006202 ATM Proteins 0.000 description 4
- 102100011565 AXL Human genes 0.000 description 4
- 102100009752 BAK1 Human genes 0.000 description 4
- 101700005790 BAK1 Proteins 0.000 description 4
- 102100013894 BCL2 Human genes 0.000 description 4
- 108060000885 BCL2 Proteins 0.000 description 4
- 102200055464 BRAF V600E Human genes 0.000 description 4
- 102100019530 CCND2 Human genes 0.000 description 4
- 102100016486 CCND3 Human genes 0.000 description 4
- 102100016489 CCNE2 Human genes 0.000 description 4
- 101700041341 CCNE2 Proteins 0.000 description 4
- 108030003690 EC 2.7.1.153 Proteins 0.000 description 4
- 102000027763 FGFR4 Human genes 0.000 description 4
- 102100006565 FLT1 Human genes 0.000 description 4
- 101710030892 FLT1 Proteins 0.000 description 4
- 102100019517 JAK1 Human genes 0.000 description 4
- 102100019516 JAK2 Human genes 0.000 description 4
- 101710030888 KDR Proteins 0.000 description 4
- 108060004270 LAG3 Proteins 0.000 description 4
- 102100017213 LAG3 Human genes 0.000 description 4
- 108010068342 MAP Kinase Kinase 1 Proteins 0.000 description 4
- 102100006473 MAP2K1 Human genes 0.000 description 4
- 102100003433 MAP3K2 Human genes 0.000 description 4
- 101710039092 MAP3K2 Proteins 0.000 description 4
- 102100003434 MAP3K3 Human genes 0.000 description 4
- 102100003435 MAP3K4 Human genes 0.000 description 4
- 102100004939 PDGFRB Human genes 0.000 description 4
- 102100006771 PKM Human genes 0.000 description 4
- 101710039160 PKM Proteins 0.000 description 4
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 4
- 102000001253 Protein Kinases Human genes 0.000 description 4
- 102100003126 RAD54B Human genes 0.000 description 4
- 101710002793 RAD54B Proteins 0.000 description 4
- 102100012952 RAD54L Human genes 0.000 description 4
- 101710017584 RAD54L Proteins 0.000 description 4
- 102100015931 SMO Human genes 0.000 description 4
- 101700038204 TGFA Proteins 0.000 description 4
- 102100014223 TGFA Human genes 0.000 description 4
- 101700061326 TSC1 Proteins 0.000 description 4
- 102100015249 VEGFA Human genes 0.000 description 4
- 102100015207 VEGFB Human genes 0.000 description 4
- 102100015206 VEGFC Human genes 0.000 description 4
- 102100015205 VEGFD Human genes 0.000 description 4
- 239000004037 angiogenesis inhibitor Substances 0.000 description 4
- 229940121369 angiogenesis inhibitors Drugs 0.000 description 4
- 230000033228 biological regulation Effects 0.000 description 4
- 230000003197 catalytic Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000002955 immunomodulating agent Substances 0.000 description 4
- 230000002584 immunomodulator Effects 0.000 description 4
- 229940121354 immunomodulators Drugs 0.000 description 4
- 238000002372 labelling Methods 0.000 description 4
- 230000001394 metastastic Effects 0.000 description 4
- 230000000869 mutational Effects 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 230000003612 virological Effects 0.000 description 4
- 101710043085 ADAM17 Proteins 0.000 description 3
- 102100007747 ANGPT2 Human genes 0.000 description 3
- 102100001329 ANGPT4 Human genes 0.000 description 3
- 102100006650 AREG Human genes 0.000 description 3
- 101700032749 AREG Proteins 0.000 description 3
- 101700033894 ATRX Proteins 0.000 description 3
- 101710039535 AXL Proteins 0.000 description 3
- 101700008384 AXL1 Proteins 0.000 description 3
- 102100004344 BORA Human genes 0.000 description 3
- 108060000973 BORA Proteins 0.000 description 3
- 108010042977 BRCA1 Protein Proteins 0.000 description 3
- 102100001432 BTC Human genes 0.000 description 3
- 101700038892 BTC Proteins 0.000 description 3
- 102100019529 CCND1 Human genes 0.000 description 3
- 101700059002 CCND2 Proteins 0.000 description 3
- 101700079292 CCND3 Proteins 0.000 description 3
- 102100016490 CCNE1 Human genes 0.000 description 3
- 101700061678 CCNE1 Proteins 0.000 description 3
- 102100006130 CDK6 Human genes 0.000 description 3
- 108010058546 Cyclin D1 Proteins 0.000 description 3
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 3
- 102100014098 DKC1 Human genes 0.000 description 3
- 101700033980 DKC1 Proteins 0.000 description 3
- 101700033006 EGF Proteins 0.000 description 3
- 102100010813 EGF Human genes 0.000 description 3
- 102200048795 EGFR G719A Human genes 0.000 description 3
- 101700024891 EPHB2 Proteins 0.000 description 3
- 102100016662 ERBB2 Human genes 0.000 description 3
- 101700025368 ERBB2 Proteins 0.000 description 3
- 102000027777 ERBB4 Human genes 0.000 description 3
- 101700023619 ERBB4 Proteins 0.000 description 3
- 102100010867 ERCC1 Human genes 0.000 description 3
- 101700054147 ERCC1 Proteins 0.000 description 3
- 101700072570 EREG Proteins 0.000 description 3
- 102100019146 EREG Human genes 0.000 description 3
- 102000027758 FGFR1 Human genes 0.000 description 3
- 102000027765 FGFR2 Human genes 0.000 description 3
- 102000027766 FGFR3 Human genes 0.000 description 3
- 101700075612 FGFR4 Proteins 0.000 description 3
- 102100013182 FLT4 Human genes 0.000 description 3
- 102100006432 FZD1 Human genes 0.000 description 3
- 101700058700 FZD1 Proteins 0.000 description 3
- 102100006430 FZD5 Human genes 0.000 description 3
- 101700006675 FZD5 Proteins 0.000 description 3
- 102100016400 HBEGF Human genes 0.000 description 3
- 101700029736 HBEGF Proteins 0.000 description 3
- 102100016432 HDAC2 Human genes 0.000 description 3
- 102100016431 HDAC3 Human genes 0.000 description 3
- 102100000579 HGF Human genes 0.000 description 3
- 102100009283 HRAS Human genes 0.000 description 3
- 101710033925 HRAS Proteins 0.000 description 3
- 102100008717 ILK Human genes 0.000 description 3
- 101710010714 INSR Proteins 0.000 description 3
- 102100006542 JAG1 Human genes 0.000 description 3
- 101700034277 JAK1 Proteins 0.000 description 3
- 101700016050 JAK2 Proteins 0.000 description 3
- 102200006539 KRAS G12D Human genes 0.000 description 3
- 102100019632 KSR1 Human genes 0.000 description 3
- 210000004072 Lung Anatomy 0.000 description 3
- 108010068353 MAP Kinase Kinase 2 Proteins 0.000 description 3
- 108010075654 MAP Kinase Kinase Kinase 1 Proteins 0.000 description 3
- 102100015877 MAP2K2 Human genes 0.000 description 3
- 102100015875 MAP2K3 Human genes 0.000 description 3
- 101710027475 MAP2K3 Proteins 0.000 description 3
- 102100015874 MAP2K4 Human genes 0.000 description 3
- 102100016522 MAP3K1 Human genes 0.000 description 3
- 101710039099 MAP3K3 Proteins 0.000 description 3
- 101710039094 MAP3K4 Proteins 0.000 description 3
- 102100005529 MAPK11 Human genes 0.000 description 3
- 102100016825 MAPK3 Human genes 0.000 description 3
- 229920002726 Mir-31 Polymers 0.000 description 3
- 101710007214 NAE1 Proteins 0.000 description 3
- 102100014664 NAE1 Human genes 0.000 description 3
- 102100007467 NEDD8 Human genes 0.000 description 3
- 108010072790 NEDD8 Protein Proteins 0.000 description 3
- 101710036042 NOTCH1 Proteins 0.000 description 3
- 102100015654 NRG4 Human genes 0.000 description 3
- 101700056003 NRG4 Proteins 0.000 description 3
- 102100007289 PDCD1LG2 Human genes 0.000 description 3
- 102100007812 PDGFA Human genes 0.000 description 3
- 102100007815 PDGFB Human genes 0.000 description 3
- 102100004940 PDGFRA Human genes 0.000 description 3
- 101710018349 PDGFRA Proteins 0.000 description 3
- 102100019436 PLK1 Human genes 0.000 description 3
- 101700009419 PTEN Proteins 0.000 description 3
- 108050002092 RAD52 Proteins 0.000 description 3
- 102100002821 RAD52 Human genes 0.000 description 3
- 102100000895 RB1 Human genes 0.000 description 3
- 101710017811 RB1 Proteins 0.000 description 3
- 108010068097 Rad51 Recombinase Proteins 0.000 description 3
- 102000002490 Rad51 Recombinase Human genes 0.000 description 3
- 102100019657 STAT1 Human genes 0.000 description 3
- 102100019656 STAT2 Human genes 0.000 description 3
- 102100019667 STAT3 Human genes 0.000 description 3
- 108010017324 STAT3 Transcription Factor Proteins 0.000 description 3
- 102100019330 STK11 Human genes 0.000 description 3
- 101700065463 STK11 Proteins 0.000 description 3
- 102100002798 STK36 Human genes 0.000 description 3
- 101700028167 STK36 Proteins 0.000 description 3
- 101700004103 TEP1 Proteins 0.000 description 3
- 108010081291 Type 1 Fibroblast Growth Factor Receptor Proteins 0.000 description 3
- 108010081268 Type 2 Fibroblast Growth Factor Receptor Proteins 0.000 description 3
- 108010081267 Type 3 Fibroblast Growth Factor Receptor Proteins 0.000 description 3
- 102100017305 UBA1 Human genes 0.000 description 3
- 101700019707 UBA1 Proteins 0.000 description 3
- 101700068732 VEGFA Proteins 0.000 description 3
- 101700070240 VEGFB Proteins 0.000 description 3
- 101700082383 VEGFC Proteins 0.000 description 3
- 101700020875 VEGFD Proteins 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000000890 drug combination Substances 0.000 description 3
- 238000009114 investigational therapy Methods 0.000 description 3
- 101700085186 lcb2 Proteins 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 108010017843 platelet-derived growth factor A Proteins 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 108010057210 telomerase RNA Proteins 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 238000011144 upstream manufacturing Methods 0.000 description 3
- GYLDXIAOMVERTK-UHFFFAOYSA-N 5-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1,3-benzoxazol-2-amine Chemical compound C12=C(N)N=CN=C2N(C(C)C)N=C1C1=CC=C(OC(N)=N2)C2=C1 GYLDXIAOMVERTK-UHFFFAOYSA-N 0.000 description 2
- 102100001250 AKT2 Human genes 0.000 description 2
- 101700006583 AKT2 Proteins 0.000 description 2
- 102100007742 ANGPT1 Human genes 0.000 description 2
- 101710043855 ANGPT2 Proteins 0.000 description 2
- 101710043859 ANGPT4 Proteins 0.000 description 2
- 102100001079 APH1A Human genes 0.000 description 2
- 101700024087 APH1A Proteins 0.000 description 2
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 description 2
- 208000009956 Adenocarcinoma Diseases 0.000 description 2
- 241000271566 Aves Species 0.000 description 2
- 102100015655 BCL2L1 Human genes 0.000 description 2
- 101710032374 BCL2L1 Proteins 0.000 description 2
- 101700076604 BRCA1 Proteins 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 102100004728 CDH1 Human genes 0.000 description 2
- 101700016900 CDH1 Proteins 0.000 description 2
- 102000033243 CDKN2A Human genes 0.000 description 2
- 102100019698 CHEK2 Human genes 0.000 description 2
- 108060006647 CHEK2 Proteins 0.000 description 2
- 102100001886 CTNNA1 Human genes 0.000 description 2
- 101710005993 CTNNA1 Proteins 0.000 description 2
- 102100002043 CTNNB1 Human genes 0.000 description 2
- 101710005974 CTNNB1 Proteins 0.000 description 2
- 230000036874 Clup Effects 0.000 description 2
- 210000001072 Colon Anatomy 0.000 description 2
- 241000699800 Cricetinae Species 0.000 description 2
- 241000710137 Cucumber necrosis virus Species 0.000 description 2
- 102000009512 Cyclin-Dependent Kinase Inhibitor p15 Human genes 0.000 description 2
- 108010009356 Cyclin-Dependent Kinase Inhibitor p15 Proteins 0.000 description 2
- 108010009392 Cyclin-Dependent Kinase Inhibitor p16 Proteins 0.000 description 2
- 238000000018 DNA microarray Methods 0.000 description 2
- 108010029190 EC 2.7.1.67 Proteins 0.000 description 2
- 102000001556 EC 2.7.1.67 Human genes 0.000 description 2
- 102200048951 EGFR S768I Human genes 0.000 description 2
- 102000027776 ERBB3 Human genes 0.000 description 2
- 101700041204 ERBB3 Proteins 0.000 description 2
- 102100015611 FGF14 Human genes 0.000 description 2
- 101700085636 FGF14 Proteins 0.000 description 2
- 102100007408 FGF5 Human genes 0.000 description 2
- 101700010264 FGF5 Proteins 0.000 description 2
- 102100007407 FGF6 Human genes 0.000 description 2
- 101700012851 FGF6 Proteins 0.000 description 2
- 102100007405 FGF7 Human genes 0.000 description 2
- 101700033323 FGF7 Proteins 0.000 description 2
- 102100015613 FGF8 Human genes 0.000 description 2
- 101700012405 FGF8 Proteins 0.000 description 2
- 102000003971 Fibroblast Growth Factor 1 Human genes 0.000 description 2
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 2
- 102100006425 GAPDH Human genes 0.000 description 2
- 101710008404 GAPDH Proteins 0.000 description 2
- 206010017758 Gastric cancer Diseases 0.000 description 2
- 206010064571 Gene mutation Diseases 0.000 description 2
- 101700061787 HDAC2 Proteins 0.000 description 2
- 101700081813 HDAC3 Proteins 0.000 description 2
- 102100016430 HDAC4 Human genes 0.000 description 2
- 101700050702 HDAC4 Proteins 0.000 description 2
- 102100007188 HDAC5 Human genes 0.000 description 2
- 101700054126 HDAC5 Proteins 0.000 description 2
- 102100017052 HSP90AA1 Human genes 0.000 description 2
- 101710033238 HSP90AA1 Proteins 0.000 description 2
- WZUVPPKBWHMQCE-XJKSGUPXSA-N Haematoxylin Natural products C12=CC(O)=C(O)C=C2C[C@]2(O)[C@H]1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-XJKSGUPXSA-N 0.000 description 2
- 102100005117 IGF2 Human genes 0.000 description 2
- 101700054549 INSC Proteins 0.000 description 2
- 102100013321 INSR Human genes 0.000 description 2
- 101700058295 JAG1 Proteins 0.000 description 2
- 102200006537 KRAS G12A Human genes 0.000 description 2
- 102200007373 KRAS Q61H Human genes 0.000 description 2
- 101700047952 KSR1 Proteins 0.000 description 2
- 206010024324 Leukaemias Diseases 0.000 description 2
- 206010050017 Lung cancer metastatic Diseases 0.000 description 2
- 101710027749 MAP2K4 Proteins 0.000 description 2
- 101710029925 MAPK11 Proteins 0.000 description 2
- 101700001448 MAPK3 Proteins 0.000 description 2
- 101700068368 MCD1 Proteins 0.000 description 2
- 101710026102 MIC-ACT-2 Proteins 0.000 description 2
- 101700072814 MPK12 Proteins 0.000 description 2
- 101700067592 MST1 Proteins 0.000 description 2
- 101710026284 NCSTN Proteins 0.000 description 2
- 102100020198 NCSTN Human genes 0.000 description 2
- 101700063429 NID1 Proteins 0.000 description 2
- 102100015657 NRG2 Human genes 0.000 description 2
- 101700080329 NRG2 Proteins 0.000 description 2
- 102400000058 Neuregulin-1 Human genes 0.000 description 2
- 108090000556 Neuregulin-1 Proteins 0.000 description 2
- 210000001672 Ovary Anatomy 0.000 description 2
- 206010063834 Oversensing Diseases 0.000 description 2
- 102100014579 PARP1 Human genes 0.000 description 2
- 101710011976 PDCD1LG2 Proteins 0.000 description 2
- 102100016457 PIM1 Human genes 0.000 description 2
- 101700018532 PIM1 Proteins 0.000 description 2
- 101700062434 PLK1 Proteins 0.000 description 2
- 101710025128 PRKACA Proteins 0.000 description 2
- 101710033350 PSEN1 Proteins 0.000 description 2
- 102100008812 PSEN1 Human genes 0.000 description 2
- 102100004316 PTGES3 Human genes 0.000 description 2
- 101710036259 PTGES3 Proteins 0.000 description 2
- 108010065129 Patched-1 Receptor Proteins 0.000 description 2
- 102000012850 Patched-1 Receptor Human genes 0.000 description 2
- 108091000081 Phosphotransferases Proteins 0.000 description 2
- 108010051742 Platelet-Derived Growth Factor beta Receptor Proteins 0.000 description 2
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 2
- 108060006633 Protein Kinases Proteins 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 108010019674 Proto-Oncogene Proteins c-sis Proteins 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 102100005349 SOCS1 Human genes 0.000 description 2
- 102100019815 SRRT Human genes 0.000 description 2
- 101700037877 SRRT Proteins 0.000 description 2
- 108010044012 STAT1 Transcription Factor Proteins 0.000 description 2
- 108010081691 STAT2 Transcription Factor Proteins 0.000 description 2
- 102100019671 STK4 Human genes 0.000 description 2
- 101700023684 STK4 Proteins 0.000 description 2
- 102100004542 SUFU Human genes 0.000 description 2
- 108060007940 SUFU Proteins 0.000 description 2
- 101710019450 TARS2 Proteins 0.000 description 2
- 108010044281 TATA-Box Binding Protein Proteins 0.000 description 2
- 102000012235 TATA-box binding protein Human genes 0.000 description 2
- 101700041213 TGFB1 Proteins 0.000 description 2
- 102100014320 TGFB1 Human genes 0.000 description 2
- 102100011242 THBS1 Human genes 0.000 description 2
- 102100008210 TSC2 Human genes 0.000 description 2
- 101700083014 TSC2 Proteins 0.000 description 2
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 description 2
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 2
- 102100002579 WEE1 Human genes 0.000 description 2
- 108060006684 WEE1 Proteins 0.000 description 2
- 102100013395 WNT5A Human genes 0.000 description 2
- 101700008653 WNT5A Proteins 0.000 description 2
- 108010062203 Wnt1 Protein Proteins 0.000 description 2
- 102000011777 Wnt1 Protein Human genes 0.000 description 2
- 108010000443 X-ray Repair Cross Complementing Protein 1 Proteins 0.000 description 2
- 102000002258 X-ray Repair Cross Complementing Protein 1 Human genes 0.000 description 2
- 102100009955 XRCC4 Human genes 0.000 description 2
- 108060009531 XRCC4 Proteins 0.000 description 2
- 101700078629 YWP1 Proteins 0.000 description 2
- 230000000240 adjuvant Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 230000000259 anti-tumor Effects 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 231100000005 chromosome aberration Toxicity 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000002074 deregulated Effects 0.000 description 2
- 230000003831 deregulation Effects 0.000 description 2
- 229950008597 drug INN Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000003511 endothelial Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002449 erythroblastic Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 102000003684 fibroblast growth factor 13 Human genes 0.000 description 2
- 108090000047 fibroblast growth factor 13 Proteins 0.000 description 2
- 230000001965 increased Effects 0.000 description 2
- 125000001261 isocyanato group Chemical group *N=C=O 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 101700064822 lcb1 Proteins 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 101710031797 mst101(1) Proteins 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 102220014453 rs397517119 Human genes 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- MCUJKPPARUPFJM-UWCCDQBKSA-N (5Z)-5-[[2-[(3R)-3-aminopiperidin-1-yl]-3-phenylphenyl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C1[C@H](N)CCCN1C(C(=CC=C1)C=2C=CC=CC=2)=C1\C=C/1C(=O)NC(=O)S\1 MCUJKPPARUPFJM-UWCCDQBKSA-N 0.000 description 1
- BKWJAKQVGHWELA-UHFFFAOYSA-N 1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-6-[4-(4-methylpiperazin-1-yl)anilino]-2-prop-2-enylpyrazolo[3,4-d]pyrimidin-3-one Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC=C2C(=O)N(CC=C)N(C=3N=C(C=CC=3)C(C)(C)O)C2=N1 BKWJAKQVGHWELA-UHFFFAOYSA-N 0.000 description 1
- JUSFANSTBFGBAF-IRXDYDNUSA-N 3-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-N-methylbenzamide Chemical compound CNC(=O)C1=CC=CC(C=2N=C3N=C(N=C(C3=CC=2)N2[C@H](COCC2)C)N2[C@H](COCC2)C)=C1 JUSFANSTBFGBAF-IRXDYDNUSA-N 0.000 description 1
- JDUBGYFRJFOXQC-KRWDZBQOSA-N 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide Chemical compound C1([C@H](CCO)NC(=O)C2(CCN(CC2)C=2C=3C=CNC=3N=CN=2)N)=CC=C(Cl)C=C1 JDUBGYFRJFOXQC-KRWDZBQOSA-N 0.000 description 1
- LMJFJIDLEAWOQJ-CQSZACIVSA-N 8-[(1R)-1-(3,5-difluoroanilino)ethyl]-N,N-dimethyl-2-morpholin-4-yl-4-oxochromene-6-carboxamide Chemical compound N([C@H](C)C=1C2=C(C(C=C(O2)N2CCOCC2)=O)C=C(C=1)C(=O)N(C)C)C1=CC(F)=CC(F)=C1 LMJFJIDLEAWOQJ-CQSZACIVSA-N 0.000 description 1
- 102100010284 ADAM17 Human genes 0.000 description 1
- 101710028150 AHCY Proteins 0.000 description 1
- 102100011248 ANGPTL1 Human genes 0.000 description 1
- 101710043876 ANGPTL1 Proteins 0.000 description 1
- 102100006824 ATR Human genes 0.000 description 1
- 108060000721 ATR Proteins 0.000 description 1
- 108010053054 Agouti-Related Protein Proteins 0.000 description 1
- 102000016552 Agouti-Related Protein Human genes 0.000 description 1
- ZLHFILGSQDJULK-UHFFFAOYSA-N Alisertib Chemical compound C1=C(C(O)=O)C(OC)=CC(NC=2N=C3C4=CC=C(Cl)C=C4C(=NCC3=CN=2)C=2C(=CC=CC=2F)OC)=C1 ZLHFILGSQDJULK-UHFFFAOYSA-N 0.000 description 1
- 108010005474 Anaplastic Lymphoma Kinase Proteins 0.000 description 1
- 108010048154 Angiopoietin-1 Proteins 0.000 description 1
- 108010048036 Angiopoietin-2 Proteins 0.000 description 1
- 206010059512 Apoptosis Diseases 0.000 description 1
- 102000003989 Aurora Kinases Human genes 0.000 description 1
- 108090000433 Aurora Kinases Proteins 0.000 description 1
- 102100007326 BIRC5 Human genes 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 210000000481 Breast Anatomy 0.000 description 1
- 210000001217 Buttocks Anatomy 0.000 description 1
- 101700086504 CBF5 Proteins 0.000 description 1
- 102100009587 CDC42EP3 Human genes 0.000 description 1
- 102100019702 CHEK1 Human genes 0.000 description 1
- 101710015564 CHEK1 Proteins 0.000 description 1
- 101710005992 CTNNA3 Proteins 0.000 description 1
- 108010019244 Checkpoint Kinase 1 Proteins 0.000 description 1
- 102000006459 Checkpoint Kinase 1 Human genes 0.000 description 1
- 210000003483 Chromatin Anatomy 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- 210000000349 Chromosomes Anatomy 0.000 description 1
- 229920001405 Coding region Polymers 0.000 description 1
- 229920002676 Complementary DNA Polymers 0.000 description 1
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 1
- 108010058544 Cyclin D2 Proteins 0.000 description 1
- 108010058545 Cyclin D3 Proteins 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 102000003903 Cyclin-Dependent Kinases Human genes 0.000 description 1
- 108090000266 Cyclin-Dependent Kinases Proteins 0.000 description 1
- 101700011568 DIB1 Proteins 0.000 description 1
- 102100015284 DKK1 Human genes 0.000 description 1
- 101700029587 DKK1 Proteins 0.000 description 1
- BFSMGDJOXZAERB-UHFFFAOYSA-N Dabrafenib Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 BFSMGDJOXZAERB-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 101700039191 EGFR Proteins 0.000 description 1
- 102200048928 EGFR L858R Human genes 0.000 description 1
- 102200048955 EGFR T790M Human genes 0.000 description 1
- 229940121647 EGFR inhibitors Drugs 0.000 description 1
- 229940116977 Epidermal Growth Factor Drugs 0.000 description 1
- 229940109526 Ery Drugs 0.000 description 1
- 102000027757 FGF receptors Human genes 0.000 description 1
- 108091008101 FGF receptors Proteins 0.000 description 1
- 102100007155 FGF1 Human genes 0.000 description 1
- 101700064732 FGF1 Proteins 0.000 description 1
- 102100000261 FGF10 Human genes 0.000 description 1
- 101700052889 FGF10 Proteins 0.000 description 1
- 102100000262 FGF11 Human genes 0.000 description 1
- 101700050155 FGF11 Proteins 0.000 description 1
- 102100000263 FGF12 Human genes 0.000 description 1
- 101700081916 FGF12 Proteins 0.000 description 1
- 102100015616 FGF18 Human genes 0.000 description 1
- 101700001573 FGF18 Proteins 0.000 description 1
- 102100008634 FGF2 Human genes 0.000 description 1
- 101700082364 FGF2 Proteins 0.000 description 1
- YSFTYXKQUONNFY-NQXPEFQPSA-N FGF2 Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CO)NC(=O)CNC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H]1NCCC1)C1=CC=CC=C1 YSFTYXKQUONNFY-NQXPEFQPSA-N 0.000 description 1
- 102100008645 FGF3 Human genes 0.000 description 1
- 102100007406 FGF4 Human genes 0.000 description 1
- 101700036125 FGF4 Proteins 0.000 description 1
- 102100015612 FGF9 Human genes 0.000 description 1
- 101700084870 FGF9 Proteins 0.000 description 1
- 101710030894 FLT4 Proteins 0.000 description 1
- 102000003974 Fibroblast Growth Factor 2 Human genes 0.000 description 1
- 108090000379 Fibroblast Growth Factor 2 Proteins 0.000 description 1
- 102000003975 Fibroblast Growth Factor 3 Human genes 0.000 description 1
- 108090000378 Fibroblast Growth Factor 3 Proteins 0.000 description 1
- 102000003969 Fibroblast Growth Factor 4 Human genes 0.000 description 1
- 108090000381 Fibroblast Growth Factor 4 Proteins 0.000 description 1
- 102000003967 Fibroblast Growth Factor 5 Human genes 0.000 description 1
- 108090000380 Fibroblast Growth Factor 5 Proteins 0.000 description 1
- 102000003968 Fibroblast Growth Factor 6 Human genes 0.000 description 1
- 108090000382 Fibroblast Growth Factor 6 Proteins 0.000 description 1
- 102000003972 Fibroblast Growth Factor 7 Human genes 0.000 description 1
- 108090000385 Fibroblast Growth Factor 7 Proteins 0.000 description 1
- 102000003956 Fibroblast Growth Factor 8 Human genes 0.000 description 1
- 108090000368 Fibroblast Growth Factor 8 Proteins 0.000 description 1
- 102000003957 Fibroblast Growth Factor 9 Human genes 0.000 description 1
- 108090000367 Fibroblast Growth Factor 9 Proteins 0.000 description 1
- 102000004864 Fibroblast growth factor 10 Human genes 0.000 description 1
- 108090001047 Fibroblast growth factor 10 Proteins 0.000 description 1
- 102000014252 Fibroblast growth factor 11 Human genes 0.000 description 1
- 108050003237 Fibroblast growth factor 11 Proteins 0.000 description 1
- 102000014250 Fibroblast growth factor 12 Human genes 0.000 description 1
- 108050003239 Fibroblast growth factor 12 Proteins 0.000 description 1
- 102100010306 GLI1 Human genes 0.000 description 1
- 101700009498 GLI1 Proteins 0.000 description 1
- 108091008163 GPCRs class F Proteins 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 102100002572 HDAC1 Human genes 0.000 description 1
- 101700036927 HDAC1 Proteins 0.000 description 1
- 101700036123 HGF Proteins 0.000 description 1
- 206010073069 Hepatic cancer Diseases 0.000 description 1
- 108010023981 Histone Deacetylase 2 Proteins 0.000 description 1
- 206010020243 Hodgkin's disease Diseases 0.000 description 1
- 201000006743 Hodgkin's lymphoma Diseases 0.000 description 1
- 241000282619 Hylobates lar Species 0.000 description 1
- 101700033123 IAAT Proteins 0.000 description 1
- 210000003592 IEL Anatomy 0.000 description 1
- 102100014263 IGF1R Human genes 0.000 description 1
- 101700025802 IGF1R Proteins 0.000 description 1
- 101700070236 IGF2 Proteins 0.000 description 1
- 102100013307 IGF2R Human genes 0.000 description 1
- 101710032496 IGF2R Proteins 0.000 description 1
- 101710004181 INTS2 Proteins 0.000 description 1
- 102100002729 IRS1 Human genes 0.000 description 1
- 101700048020 IRS1 Proteins 0.000 description 1
- 108060003876 Igfl Proteins 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 108090001117 Insulin-Like Growth Factor II Proteins 0.000 description 1
- 102000014429 Insulin-like growth factor Human genes 0.000 description 1
- 108050003490 Insulin-like growth factor Proteins 0.000 description 1
- 108010047319 Jagged-1 Protein Proteins 0.000 description 1
- 102000008986 Janus Human genes 0.000 description 1
- 108050000950 Janus Proteins 0.000 description 1
- 108010000837 Janus Kinase 1 Proteins 0.000 description 1
- 108010019437 Janus Kinase 2 Proteins 0.000 description 1
- 102100017012 KIF11 Human genes 0.000 description 1
- 101700069373 KIF11 Proteins 0.000 description 1
- 102200007380 KRAS A59T Human genes 0.000 description 1
- 102200006538 KRAS G12C Human genes 0.000 description 1
- 102200006540 KRAS G12R Human genes 0.000 description 1
- 102200006541 KRAS G12S Human genes 0.000 description 1
- 102200006532 KRAS G13D Human genes 0.000 description 1
- 102200006520 KRAS Q61L Human genes 0.000 description 1
- 102200006525 KRAS Q61R Human genes 0.000 description 1
- 108010003046 KSR-1 protein kinase Proteins 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 101710036514 LONP1 Proteins 0.000 description 1
- 210000004185 Liver Anatomy 0.000 description 1
- 108010075645 MAP Kinase Kinase Kinase 3 Proteins 0.000 description 1
- 108010075647 MAP Kinase Kinase Kinase 4 Proteins 0.000 description 1
- 102100012607 MAP2K6 Human genes 0.000 description 1
- 101710027753 MAP2K6 Proteins 0.000 description 1
- 101700064507 MARK2 Proteins 0.000 description 1
- 102100001008 MET Human genes 0.000 description 1
- 102100003099 MST1R Human genes 0.000 description 1
- 101710029065 MST1R Proteins 0.000 description 1
- 101700036611 MTOR Proteins 0.000 description 1
- 108010087267 Mitogen-Activated Protein Kinase 1 Proteins 0.000 description 1
- 108010081247 Mitogen-Activated Protein Kinase 11 Proteins 0.000 description 1
- 108010087271 Mitogen-Activated Protein Kinase 3 Proteins 0.000 description 1
- 241000713333 Mouse mammary tumor virus Species 0.000 description 1
- 210000003205 Muscles Anatomy 0.000 description 1
- 229920001850 Nucleic acid sequence Polymers 0.000 description 1
- FAQDUNYVKQKNLD-UHFFFAOYSA-N Olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 1
- 229920000272 Oligonucleotide Polymers 0.000 description 1
- 108010053291 Oncogene Protein v-akt Proteins 0.000 description 1
- 101710016786 P/C Proteins 0.000 description 1
- 101710018346 PDGFRB Proteins 0.000 description 1
- 102100019471 PIK3CA Human genes 0.000 description 1
- 101710027440 PIK3CA Proteins 0.000 description 1
- 102200085788 PIK3CA H1047L Human genes 0.000 description 1
- 102200085789 PIK3CA H1047R Human genes 0.000 description 1
- 101700086880 PIM2 Proteins 0.000 description 1
- 102100016471 PIM2 Human genes 0.000 description 1
- 101700060421 PIM3 Proteins 0.000 description 1
- 102100016470 PIM3 Human genes 0.000 description 1
- 101700005340 PLK Proteins 0.000 description 1
- 210000000496 Pancreas Anatomy 0.000 description 1
- 208000008443 Pancreatic Carcinoma Diseases 0.000 description 1
- 102000007982 Phosphoproteins Human genes 0.000 description 1
- 108010014866 Programmed Cell Death 1 Ligand 2 Protein Proteins 0.000 description 1
- 108010080196 Programmed Cell Death 1 Receptor Proteins 0.000 description 1
- 101710037934 QRSL1 Proteins 0.000 description 1
- 102100009211 RABL6 Human genes 0.000 description 1
- 101700084710 RABL6 Proteins 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 101710007825 RNASE3 Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 210000003705 Ribosomes Anatomy 0.000 description 1
- 102100018013 SHH Human genes 0.000 description 1
- 101700020958 SHH Proteins 0.000 description 1
- 101700001014 SLTM Proteins 0.000 description 1
- 101700021542 SMO Proteins 0.000 description 1
- 101700076839 SMOX Proteins 0.000 description 1
- 102100019538 SOS1 Human genes 0.000 description 1
- 101700043907 STAT1 Proteins 0.000 description 1
- 101700054244 STAT2 Proteins 0.000 description 1
- 210000002784 Stomach Anatomy 0.000 description 1
- 108010089643 Suppressor of Cytokine Signaling 1 Protein Proteins 0.000 description 1
- 108010002687 Survivin Proteins 0.000 description 1
- 210000000400 T-Lymphocytes, Cytotoxic Anatomy 0.000 description 1
- 102100018596 TEP1 Human genes 0.000 description 1
- 101710041009 THBS1 Proteins 0.000 description 1
- 108010046722 Thrombospondin 1 Proteins 0.000 description 1
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 1
- 206010044696 Tropical spastic paresis Diseases 0.000 description 1
- 208000004697 Tuberous Sclerosis 1 Diseases 0.000 description 1
- 108010081264 Type 4 Fibroblast Growth Factor Receptor Proteins 0.000 description 1
- 102400000757 Ubiquitin Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 108091007928 VEGF receptors Proteins 0.000 description 1
- 101700021643 VP4A Proteins 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 108010073925 Vascular Endothelial Growth Factor B Proteins 0.000 description 1
- 108010073923 Vascular Endothelial Growth Factor C Proteins 0.000 description 1
- 108010073919 Vascular Endothelial Growth Factor D Proteins 0.000 description 1
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 101700006396 WIF1 Proteins 0.000 description 1
- 102100010144 WIF1 Human genes 0.000 description 1
- 101700061199 WNT1 Proteins 0.000 description 1
- 102100000447 WNT1 Human genes 0.000 description 1
- 101700080705 WNT5B Proteins 0.000 description 1
- 102100015179 WNT5B Human genes 0.000 description 1
- 108010021176 Wnt-5a Protein Proteins 0.000 description 1
- 102000008223 Wnt-5a Protein Human genes 0.000 description 1
- 108010085257 X-Linked Inhibitor of Apoptosis Protein Proteins 0.000 description 1
- 102100010212 XIAP Human genes 0.000 description 1
- MPUQHZXIXSTTDU-QXGSTGNESA-N [(1S,2S,4R)-4-[4-[[(1S)-2,3-dihydro-1H-inden-1-yl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound C1[C@H](O)[C@H](COS(=O)(=O)N)C[C@H]1N1C2=NC=NC(N[C@@H]3C4=CC=CC=C4CC3)=C2C=C1 MPUQHZXIXSTTDU-QXGSTGNESA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000000996 additive Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 108010069801 angiopoietin 4 Proteins 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229960000070 antineoplastic Monoclonal antibodies Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000003190 augmentative Effects 0.000 description 1
- 108010023337 axl receptor tyrosine kinase Proteins 0.000 description 1
- 230000033590 base-excision repair Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000000903 blocking Effects 0.000 description 1
- 201000005216 brain cancer Diseases 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000001413 cellular Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000002759 chromosomal Effects 0.000 description 1
- 201000011231 colorectal cancer Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 229960002465 dabrafenib Drugs 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000010228 ex vivo assay Methods 0.000 description 1
- 102000003685 fibroblast growth factor 14 Human genes 0.000 description 1
- 108090000046 fibroblast growth factor 14 Proteins 0.000 description 1
- 229940098448 fibroblast growth factor 7 Drugs 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 125000000267 glycino group Chemical group [H]N([*])C([H])([H])C(=O)O[H] 0.000 description 1
- 238000009499 grossing Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 108010074724 histone deacetylase 3 Proteins 0.000 description 1
- 230000002519 immonomodulatory Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 229940068935 insulin-like growth factor 2 Drugs 0.000 description 1
- 108010059517 integrin-linked kinase Proteins 0.000 description 1
- 201000001091 isolated ectopia lentis Diseases 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 244000145841 kine Species 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 201000002250 liver carcinoma Diseases 0.000 description 1
- 230000002934 lysing Effects 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229920005626 miR-380 Polymers 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 108010045030 monoclonal antibodies Proteins 0.000 description 1
- 229960000060 monoclonal antibodies Drugs 0.000 description 1
- 102000005614 monoclonal antibodies Human genes 0.000 description 1
- 102000004166 nicastrin protein Human genes 0.000 description 1
- 108091000431 nicastrin protein Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical group 0.000 description 1
- 229960000572 olaparib Drugs 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 230000036961 partial Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 108010056274 polo-like kinase 1 Proteins 0.000 description 1
- 229920000740 poly(D-lysine) polymer Polymers 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 230000002104 routine Effects 0.000 description 1
- 102220216298 rs1060503367 Human genes 0.000 description 1
- 102220226472 rs1064793838 Human genes 0.000 description 1
- 102220005774 rs121913438 Human genes 0.000 description 1
- 102220052696 rs121913442 Human genes 0.000 description 1
- 102220052592 rs121913463 Human genes 0.000 description 1
- 102220014622 rs17849079 Human genes 0.000 description 1
- 102220005775 rs397509368 Human genes 0.000 description 1
- 102220014422 rs397517094 Human genes 0.000 description 1
- 102220039812 rs587778038 Human genes 0.000 description 1
- 102220052587 rs727504278 Human genes 0.000 description 1
- 102220097976 rs753257724 Human genes 0.000 description 1
- 102220164837 rs755999183 Human genes 0.000 description 1
- 102220091421 rs876657848 Human genes 0.000 description 1
- 230000011218 segmentation Effects 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000000391 smoking Effects 0.000 description 1
- 230000004936 stimulating Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 230000001360 synchronised Effects 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 102000003995 transcription factors Human genes 0.000 description 1
- 108090000464 transcription factors Proteins 0.000 description 1
- 238000009966 trimming Methods 0.000 description 1
- 210000004881 tumor cells Anatomy 0.000 description 1
- 238000004450 types of analysis Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 101700014106 y12A Proteins 0.000 description 1
Abstract
The present invention relates to a method for determining the best combinations of at least three drugs for treating cancer, which is based on the determination of the most relevant intervention points for an individual.
Description
METHOD FOR SELECTING PERSONALIZED TRl-THERAPY FOR CANCER TREATMENT
FIELD OF THE INVENTION
The present invention relates to the field on gy, especially to personalized medicine in
cancer therapy. More particularly, it relates a new concept of therapeutic approach, the
triple regimen therapy and method for selecting the most appropriate combinations of drugs
for treating cancer in a ular subject.
BACKGROUND OF THE INVENTION
Lung cancer is the most common malignancy worldwide with a staggering 1.8 million cases
diagnosed per year. Over half of NSCLC are diagnosed at the metastatic stage. Even utilizing
the standard of care in the Western world, consisting mainly of chemotherapeutic agents
and radiation therapy, there has been little impact on mortality, with only 30% of all patients
diagnosed (regardless of stage) alive at one year, and a dismal 1 and 5 year survival rates of
about 8-15% and 4%, tively for those with metastatic disease. For patients that have
failed first line therapy, the median survival is only about 7 months.
Progress brought by targeted therapies such as matching EGFR activating mutations or ALK
ocation have shown substantial response rates, demonstrating the potency of
molecularly-matched targeted therapy, but erapies such as these apply to only small
subsets of patients, and virtually all patients develop resistance and succumb to their
disease. This is s not cted, as patients often harbor multiple lar
aberrations that require prosecution. The power of combination therapy has been
illustrated in diseases such as Hodgkin’s lymphoma where cure was effected by
combinations. Further in the modern era of targeted therapy, combinations targeting the
same pathway (e.g. trametanib (MEK) inhibitor er with dabrafenib (BRAF inhibitor) in
BRAF-mutant ma, or resistance pathways ning PIK3CA and MEK inhibitors) are
y being tested and have shown efficacy, in some cases, but no cure and no significant
impact on survival. Combinations of targeted therapy in NSCLC have, however, to date,
been very limited in scope.
Personalized medicine today offers modest benefits in advanced metastatic disease
(especially lung cancer). Mono-therapies have failed to cure advanced diseases. Most
combination herapies lack an underlying biologic or molecular rationale.
Therefore, there is a strong need to define, for each ic patient, the best combinations
of drugs for treating cancer.
SUMMARY OF THE ION
The ors present a novel concept of therapy in cancer, in particular metastatic lung
cancer, based on tri therapy associating three ed drugs. They created a fied
interventional mapping system (SIMS) merging knowledge from drugs and rks of
. An interventional point means a target/gene, or a group of targets/genes, activated
and that can be blocked by a drug. They described 24 interventional points based on a
collection of 183 genes. Method of investigation of status of activation of the interventional
points is based on complete genomics investigation of dual tumor and normal biopsies
matched from strictly the same points, and preferably comprise sequencing, copy number
variation gene expression and miRNA expression. An algorithm was developed to create a
scoring , e.g. from 1 to 10, enabling the ranking of the activated interventional points
in each patient.
Based on score and trends of co-activation of interventional points, the invention presents a
new scientific rationale to associate combination of therapiesAccordingly, the present
invention relates to a method for determining in a patient having a cancer a classification of
intervention points according to their activation status, wherein
- the intervention points comprise the group consisting of the HER, ,
PLK/AURK/Kinesins, Angiogenesis, Angiopoietins, Immune Modulators, PI3K,
MET, MEK, ERK, Anti-Apoptosis, FGF, mTOR, Ras/Raf, Telomerase, IGF/glycolysis,
Wnt, PARP, HDAC, JAK-STAT, Hedgehog, NOTCH pathway, DNA Repair and RET,
ALK, ROS1 and UB1, or any subgroup thereof of at least 10 intervention points;
and the genes of each intervention point are defined according to Table 1 or 9;
- the method ses
- characterizing a tumor sample in comparison to a normal histologically matched
sample from the same t, including
- for each pathway of the group or subgroup of intervention points,
determining the mRNA expression level of the genes of the intervention
point as disclosed in Table 1 or 9, y determining a fold change of
mRNA expression of tumor vs normal, (referred as mRNA TvN fold
change»
wholly or partially sequencing genes of Table 1 or 9, thereby identifying
the ce of ting mutation in the tumor ;
optionally, for each intervention point of the group or subgroup of
intervention points, determining the level of miRNAs of the genes of the
intervention point as disclosed in Table 1 or 9, thereby determining a fold
change of miRNAs level of tumor vs normal, (referred as miRNA TvN fold
change»
optionally, for each intervention point of the group or subgroup of
intervention points, determining the copy number variation of the genes
of the intervention point as disclosed in Table 1 or 9, thereby determining
a tumor vs normal fold change for the amplified genes;
— calculating a score for each pathway based on the characterization data, wherein
— if, in the tumor sample, the presence of an activating mutation of a gene
of an intervention point is detected, then a maximal score is given to the
intervention point, in particular a score of 10 if the g if from 1 to 10;
a score, preferably from 1 to 10, is calculated based on the arithmetic
mean of the mRNA TvN fold changes of the genes for each intervention
point of the group or subgroup of ention points, provided that the
mRNA TvN fold change of a gene is taken into consideration only if its
value is at least 1.3; and
— the score of each intervention point of the group or up of
ention points is either
a) the sum of the score due to the presence of an activating mutation
and the score calculated by the average of the mRNA TvN fold
changes; or
b) the score due to the presence of an activating mutation if there is
a mutation or the score calculated based on the arithmetic mean
ofthe mRNA TvN fold changes in absence of mutation; and
— classifying the intervention points ing to the calculated scores.
W0 2015/193212
Preferably, the genes of Table 10 are sequenced for detecting the presence of mutations as
defined in Table 10 and p53 gene is ced.
Preferably, for each intervention point of the group or subgroup of intervention points, the
method comprises determining the miRNAs level of the genes of the pathway as disclosed in
Table 1 or 9, in particular the level of miRNAs of the genes of the pathway as disclosed in
Table 11. More preferably, before the step of score calculation, a mean miRNAs fold change
for each gene is calculated as the average of the miRNA TvN fold changes for the gene, a
corrected mRNA TvN fold change is calculated by dividing the mRNA fold change Tumor
versus Normal of the gene (mRNA TvN fold change) by the mean fold change for the miRNAs
of the gene (mean miRNA TvN fold change), and the corrected mRNA TvN fold change of the
gene is then used to calculate the arithmetic mean of the mRNA TvN fold changes of the
genes for each intervention point. In a red embodiment, the level of miRNAs is
determined and used to calculate a corrected mRNA TvN fold change for the genes of the
following intervention points: mTOR-AKT-PTEN, RAS, ERK, P|3K and Immune Modulators.
ably, for each intervention point of the group or subgroup of intervention points, the
method comprises ining the copy number variation of the genes of the pathway as
disclosed in Table 1 or 9. More preferably, before the step of score calculation, a corrected
mRNA TvN fold change of a gene of an intervention point is calculated by multiplying the
mRNA TvN fold change of the gene by the CNV fold change of the gene, and the corrected
mRNA TvN fold change of the gene is then used to calculate the arithmetic mean of the
mRNA TvN fold changes of the genes for each intervention point.
Preferably, the subgroup of intervention points consists in the following group: Her, CDK4,6,
PLK/AURK/Kinesins, enesis, Immune tors, P|3K, MET, MEK, ERK, Anti-
Apoptosis, FGF, mTOR, Ras/Raf, IGF/glycolysis, Wnt, PARP, and DNA .
Preferably, it further comprise selecting a group of three activated or bed intervention
points in a patient having a cancer, wherein three intervention points are selected among
the intervention points having the t scores, preferably the three intervention points
having the highest scores.
The present invention also relates to a method for selecting a combination of three drugs
useful for treating a patient having a , wherein a group of three activated or disturbed
ention points are selected by the method of claim 9 and a drug is selected for each or
disturbed intervention point, thereby providing a combination of three drugs.
In addition, the present invention relates to the use of a kit for classifying pathways
according to their activation , wherein the kit comprises means for ing the
mRNA expression level of the genes of Table 1 or 9 for intervention points comprising the
group consisting of the HER, CDK4,6, PLK/AURK/Kinesins, Angiogenesis, Angiopoietins,
Immune Modulators, PI3K, MET, MEK, ERK, poptosis, FGF, mTOR, Ras/Raf,
Telomerase, IGF/glycolysis, Wnt, PARP, HDAC, JAK-STAT, Hedgehog, NOTCH pathway, DNA
Repair and Others’ (namely RET, ALK, R051 and U81), or any up thereof of at least 10
intervention points. Preferably, the kit further ses means for detecting the mutations
of Table 10. More preferably, the kit further comprises means for measuring the miRNA level
of miRNA of Table 11 for intervention points comprising the group consisting of the HER,
CDK4,6, PLK/AURK/Kinesins, Angiogenesis, Angiopoietins, Immune Modulators, PI3K, MET,
MEK, ERK, Anti-Apoptosis, FGF, mTOR, Ras/Raf, Telomerase, IGF/glycolysis, Wnt, PARP,
HDAC, JAK-STAT, Hedgehog, NOTCH, DNA Repair and Others’ (namely RET, ALK, R051 and
U81), or any subgroup thereof of at least 10 intervention points. Optionally, the kit further
comprises means for determining the copy number variation of the genes of Table 1 or 9 for
pathways comprising the group consisting of the HER, CDK4,6, PLK/AURK/Kinesins,
Angiogenesis, Angiopoietins, Immune Modulators, PI3K, MET, MEK, ERK, Anti-Apoptosis,
FGF, mTOR, Ras/Raf, Telomerase, IGF/glycolysis, Wnt, PARP, HDAC, AT, og,
NOTCH, DNA Repair and Others’ (namely RET, ALK, R051 and U81), or any subgroup thereof
of at least 10 intervention points.
Finally, the present invention s to a drugs combination for use in the treatment of
cancer, n the drugs combination is selected amoung the combinations disclosed in
Table 6, Table 7, Table 8 or selected in the group consisting of
anti PD1L + Pan RAF inhibitor + MtorP|3K inhibitor
anti PD1L + Pan RAF inhibitor + angiogenesis inhibitor
anti PD1L + Pan RAF inhibitor + MET inhibitor
anti PD1L + Pan RAF inhibitor + CDK4,6 inhibitor
anti CTLA4 + Pan RAF inhibitor + MtorP|3K inhibitor
anti CTLA4 + Pan RAF inhibitor + angiogenesis inhibitor
anti CTLA4 + Pan RAF inhibitor + MET inhibitor
anti CTLA4 + Pan RAF tor + CDK4,6 inhibitor
anti PD1L + MEK inhibitor + MtorP|3K dual inhibitor
WO 93212
anti PD1L + MEK inhibitor + angiogenesis inhibitor
anti PD1L + MEK inhibitor + MET inhibitor
anti PD1L + MEK inhibitor + CDK,-6 inhibitor
anti CTLA4 + MEK inhibitor + MtorP|3K dual inhibitor
anti CTLA4 + MEK inhibitor + MET inhibitor
anti CTLA4 + MEK inhibitor + angiogenesis inhibitor, and
anti CTLA4 + MEK tor + CDK4,6 inhibitor.
Preferably, the drugs included in the combination are selected from those sed in Table
More ably, the drugs combination is selected in the group consisting of
Medi-4736 (Astra Zeneca) + 0 (Takeda) + PF-384 (Pfizer)
Medi-4736 (Astra Zeneca) + MLN2480 (Takeda) + Axitinib (Pfizer) or
Motesanib (Takeda)
Medi-4736 (Astra Zeneca) + MLN2480 (Takeda) + Crizotinib (Pfizer)
Medi-4736 (Astra Zeneca) + MLN2480 (Takeda) + Palbociclib (Pfizer)
Tremelimumab (Astra Zeneca) + MLN2480 (Takeda) + PF-384 (Pfizer)
Tremelimumab (Astra Zeneca) + MLN2480 a) + Axitinib (Pfizer) or
Motesanib (Takeda)
Tremelimumab (Astra Zeneca) + MLN2480 (Takeda) + Crizotinib (Pfizer)
imumab (Astra ) + MLN2480 (Takeda) + Palbociclib (Pfizer)
Medi-4736 (Astra Zeneca) + Selumetinib (Astra Zeneca) + PF-384 (Pfizer)
Medi-4736 (Astra Zeneca) + Selumetinib (Astra Zeneca) + Axitinib (Pfizer) or
Motesanib (Takeda)
Medi-4736 (Astra Zeneca) + Selumetinib (Astra Zeneca) + Crizotinib (Pfizer)
Medi-4736 (Astra Zeneca) + Selumetinib (Astra Zeneca) + Palbociclib (Pfizer)
Tremelimumab (Astra Zeneca) + Selumetinib (Astra Zeneca) + PF-384 (Pfizer)
Tremelimumab (Astra Zeneca) + Selumetinib (Astra Zeneca) + Crizotinib
(Pfizer)
imumab (Astra Zeneca) + Selumetinib (Astra Zeneca) + Axitinib (Pfizer)
or Motesanib (Takeda), and
Tremelimumab (Astra Zeneca) + Selumetinib v + Palbociclib r).
Preferably, the cancer is a lung , more preferably a NSCLC.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1. The framework for cPCM. The problem is divided into 3 parts:
A. Mapping eutic efficacy to cellular components;
B. Scoring the status of ic nodes in the interventional maps defined in (A) and
(C) predicting combination efficacy
Figure 2. Flowchart of the scoring .
Figure 3. In Y: Mean fold change of differential gene expression between T and N in each
patient. In X: number of patients NB: for each graph, the order of patients is different. This
series serve as calibrator for calculation of deciles.
Figure 4. Representation 3D of the scoring system. Axis Z shows score from 1 to 10. Axis X
represents and example of interventional points, axis y represents each patiennt
DETAILED DESCRIPTION OF THE INVENTION
General Concept
Since monotherapies fails to cure metastatic lung cancer diseases, and dual ations
reported today on other es does not imact significantly survival, the inventors envision
applying tri-therapy, following the ical success in AIDS.
The challenge raised by the invention is choosing triple drug combinations that can benefit a
patient.
0 Single drugs are doing poorly; patients respond but ably relapse, often within a
few months. Based on the molecular complexity of metastatic disease, combinations
are needed. This situation may be analogous to that with AIDS, wherein single agents
resulted in incremental effects, but ation of three drugs has demonstrated
long-term benefit.
0 Unlike viruses, which always depend on the same ns, tumors are
heterogeneous and the biology is too complex for a single tri-therapy combination to
work on all tumors.
0 As a result, combinatorial precision cancer medicine (cPCM) is needed.
0 A d number of pathways may be abnormal in metastatic tumors.
The proposed approach
The inventors assert that, by reasonable assumptions, a realistic framework can be
established today that would allow useful drug combinations to be identified in a
personalized way (i.e. ng the combination to the patient based on the tumor
properties).
The main idea is to divide and conquer — proposing 3 steps:
1. Find a set of markers that are tive for specific interventional points of every
class of drugs: 24 markers covering 183 genes
2. Find a score that summarizes the behavior of these markers in a given patient that is
both comparable to other classes and is proportional to the probability that this drug
would work; and
3. Figure out how to e drugs such that the combination is common enough to
allow clinical testing yet we retain the ability to match combinations to patients with
sufficient precision.
Based on these assumptions, the inventors propose the SIMS (Simplified interventional
points mappins gystem) framework for ion combinational cancer medicine e 1).
0 First, they propose to reduce the enormous complexity of biological ys and
pathway cross-talk by devising a fied map that only concentrates on the genes
that are most indicative of drug target status. They propose to define "intervention
points", which consists of drug targets or group of targets as well as genes upstream
of the targets that together reflect a specific biological ty that is actionable
through therapeutic interventions. For example, pan-HER therapies define the HER
group of receptors and their ligands as a single intervention point (Figure 1a).
0 The second part of the work, the inventors propose a very simple approach for
prioritizing intervention points for a specific patient. The basic premise behind the
score is that, when the genes associated with an ention point are more
disturbed (in terms of sequence and/or expression level), the intervention point is
more likely to be crucial to the tumor. From this, it stems that the more disturbed the
genes of an intervention point, the more likely it is that therapeutics targeted at that
points will benefit the patient. The inventors are in the process of developing a family
of simple scores that e the level of gene sion in the tumor (relative to
matched normal control), the aberrations found in the intervention points' genes,
CNVs and miRNAs expression levels. Rank ization (in the example, using
deciles) is used to make the scores of different intervention points comparable.
Finally, given a le system for determining which drugs are more likely to benefit
the patient, a method is needed for choosing combinations that are likely to benefit
the patients. Here the inventors propose a tical approach, using a panel of 123
lung cancer patients as an e. Using the methods described above, they
describe the status of 24 intervention points in the 123 patients. From this, they
applied a knowledge-driven approach to look for drug combinations that are likely to
synergistically benefit the patient. Using a panel of experts, they fied those
pathways that ur frequently in the patients and are mechanistically
independent. To further improve the efficacy of the ed combinations, the
inventors propose augmenting the combined targeted therapies with
immunomodulating therapies (i.e. anti-CDlL and anti-CTLA). The rational behind this
combination is to reduce the chance of intolerable side effects while maintain the
predicted efficacy of a triple y regimen
Table 1 summarizes the interventional points presenting genes involved and main classes of drugs
Interventional ents of the inteventional points Drugs acting on
node interventional
points
_EGF,TGFA,AREG,EREG,HBEGF,BTC,NRGl, Dacomitinib-Panher
NRGZ,NRG4,EGFR ,ERBBZ inhibitor Pfizer
, ERBBB,ERBB4
CDK4, CDK6,CCND1, CCND2,CCND3, Palbociclib CDK4, 6
CDKN2A, CDKNZB, CCNEl, CCNE2, CCNE3, RBl inhibitor Pfizer
PLK / PLK1,AURKA,BORA,|LK,K|F11 MLN8237 (Aurora A
AURK/Kine kin inhib) Takeda
VEGFA,VEGFB,VEGFC,VEGFD,VEGFR1,VEGFR2, Axitinib GFR
VEGFR3,PDGFA,PDGFB,PDGFRA,PDGFRB,Kit Pfizer
Motesanib anti
VEGFR/PDGFR/kit
Takeda
Angiopoietins THBSl, TGFBl, ANGPTl, ANGPT2, ANGPTLl, -
ANGPT4, TlEl, TEK
PDlL, PDCDlLGZ, PDCDl, CTLA4, LAG3 Medi-4736 (PDLl)
AZ (Astra Zeneca)
AMP514 (PD1) AZ
Tremelimumab
(CTLA4) AZ
PF-05082566 (4-1
P|K3CA,P|K3CB,P|K3CD,P|K3CG,P|K3CZB,PRKCB, PF-384 PI3K/mTOR-
PRKCA,PRKCB,P|K3R1,P|K3R2,P|K3R3 inhibitor Pfizer
AZD8186 (Pl3Kb)AZ
MLN1117
(Pl3Kalpha tor)
Takeda
MET HGF,MET,AXL,MST1R inib Pfizer
nib (cMet) AZ
MLN1117, MLN0128
Takeda
MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP3K1, Selumetinib (MEK)
MAP3K2, MAP3K3, MAP3K4 AZ
MAPK3,MAPK1,KSR1,MAPK11
Anti-apoptosis BCL2,BCLXL,B|RC5,X|AP,BAK1 ,TP53
FGFl to FGF18, FGFRl, FGFR2, FGFR3, FGFR4 7 (FGFRl, 2,
3) AZ
mTOR mTor,AKT1,AKT2,PTEN PF-384 Pl3K/mTOR
,TSC1,TSC2,STK11,P|M 1,P| M2,P|M3 inhibitor Pfizer
AZD2014 (TOR
kinase) AZ
AZD5363 (AKTl, 2
,3) AZ
AZD1208 (PIM1, 2)
MLN0128
(TORCl/TORCZ)
Takeda
Ras/Raf KRAS,NRAS ,HRAS ,RAFl ,BRAF, CRAF MLN2480 (Pan-RAF
inhibitor) Ta keda
Telomerase TERT,TERC,TEP1,HSP90AA1,DKC1,PTGE53
IGF / glycolysis IGFl,|GF2,|GF1R,|GF2R,|NSR,IRSl,PKM 73 (IGF) AZ
CDHl, CTNNAl, CTNNBl, WNT 1, FZDl, WNT5A, B,
FZD5, WlFl, DKKl
PARP PARPl, BRCAl, XRCCl, RAD54L, RAD54B, ATM, Olaparib (PARP) AZ
ATR, CHEKl, CHEK2, WEEl AZD1775 (Weel) AZ
AZD6738 (ATR) AZ
HDAC HDACl, HDAC2, HDAC3, HDAC4, HDAC5
JAK-STAT JAK1,JAK2,STAT1,STAT2,STAT3,SOCSl
Hedgehog SHH,PTCH1,SMO,STK36,PRKACA,SUFU,GL|1
NOTCH NOTCH1,Adam17,PSEN1,NCSTN,JAGl,SRRT,APH1A
DNA Repair ERCC1,RAD52,XRCC4,RAD51,BRCA1,NEDD8,NAE1 MLN 4924 (NEDD8
AE) Takeda
RET, ALK, ROSl, UBl
Conclusion
The inventors propose a new therapeutic approach of triple n therapies aiming at
blocking aneously three different biologic abnormalities and reducing the chance of
developing the secondary ance. In addition, for defining a combination of drugs, the
inventors identified specific interventional points of drugs based on the pathways specifically
up-regulated in one particular patient having a cancer. They defined a simplified
interventionanl mapping system within the hallmarks of cancer including only signaling and
regulatory pathways that can be targeted with therapeutic agents. The principle of
fication is based on the activating signal that can be blocked by a class of drugs.
Indeed, the inventors reduce the enormous complexity of biological pathways and pathway
cross-talk by devising a simplified map that only concentrates on the gens that are most
indicative of drug target status defined as vention points”. These ention points
consist of drug targets or group of drug targets and some genes upstream of the drug targets
that er reflect a specific biological activity which is actionable through therapeutic
interventions. By upstream is referred to genes encoding a protein having an extracellular
activity. For ce, pan-HER therapies define the HER group of receptors and their ligands
as a single intervention point.
The inventors propose a very simple approach for prioritizing intervention points for a
specific patient. The basic premise is that, when the genes associated with an intervention
point are more disturbed (in terms of sequence and/or expression level), the intervention
point is more likely to be crucial or critical to the tumor. From this, it stems that the more
disturbed the genes of an intervention point are, the more likely it is that therapeutics
targeting that points will t the patient. Accordingly, the inventors have developped a
family of simple scores that combine the level of gene expression in the tumor (relative to
matched normal control), the ons found in the intervention points' genes, CNVs and
miRNAs expression .
Therefore, the inventors propose a method allowing the tumor terization of one
particular subject by considering its own tumor vs normal status in the most efficient way for
identifying the bed or activated intervention points and ranking them. The inventors
developed a new mathematical modelling and scoring system to give a score (e.g., of 1 to 10)
based on integration of omics data, especially gene expression, sequencing, miRNA analysis
and copy number variation ination.
Then, when the intervention points are ranked, it is possible to define one or several
combinations of drugs targeting a combination of disturbed or activated intervention points
so as to obtain the optimized therapy of cancer for this particular t. Preferably, the
combined therapy comprises or consists of three drugs targeting the most disturbed or
ted intervention points. The method may further comprise the administration of the
zed combination of drugs to said patient. Accordingly, the method leads to rational
combination therapies which are scientifically reliable and clinically feasible.
Tumour characterization
The method comprises a step of characterizing the tumor in one patient of interest. In
ular, the patient suffers from a cancer for which no effective therapy is established or
admitted by physicians. The reasons of this situation could be an ed stage of cancer,
for instance a stage with metastases, a relapsed cancer after one or several lines of
treatment, or even a cancer for which no established and ent treatment is associated
with. In particular, the cancers or tumors more ularly considered in the present
invention are lung cancer, especially NSCLC (non-small cell lung cancer), breast cancer (in
particular the triple negative breast cancer), colorectal cancers, kidney cancer, mas,
brain cancers, liver cancers, head and neck cancers, stomach cancers and ovary cancers.
Therefore, the method comprises an l step of providing samples for the t. Two
samples are necessary, namely one tumor sample and one normal sample from the same
patient. Preferably, the tumour sample and the normal sample provides from the same type
of tissue. More particularly, the tumor and normal samples are histologically d
tissues. Typically, the samples can be provided by biopsies. Non-exhaustively, examples of
pairs oftumor with corresponding histological normal reference tissue are the followings:
1. lung cancer adenocarcinomas or d metastases - bronchial normal mucosa
2. breast cancer tumors or derived metastases - normal epithelial breast cells
colon s adenocarcinomas or derived metastases - normal colon mucosa
EOP°>|FDP1PP° kidney cancers or derived metastases - normal kidney cells
melanomas or derived metastases - synchronous naevi
rhabdomyosarcomas or derived metastases - normal muscle tissue
liver carcinomas or derived metastases - normal liver cells
haryngeals tumors (ORL) - normal buccal mucosa
Stomach carcinomas or derived metastases - normal stomach mucosa
. Ovary cancer — normal Fallope tube mucosa
11. pancreatic cancers — normal parenchimatous tissue from pancreas
In order to optimize the tumor characterization, the inventors selected parameters that have
to be analysed in order to establish the status of the intervention points that can be targeted
by a class of drugs.
The inventors defined the main intervention points of interest, namely HER (Human
Epithelial Growth Factor Receptor), CDK4,6 (Cyclin-Dependent Kinase), PLK/AURK/Kinesins
(Polo-Like kinase/ Aurora Kinase/Kinesins), Angiogenesis, Angiopoietins, Immune
tors, P|3K (Phosphoinositide-3 Kinase), MET (cMET), MEK, ERK, Anti-Apoptosis, FGF
(Fibroblast Growth Factor), mTOR (mammalian target of rapamycin), Ras/Raf, Telomerase,
IGF/glycolysis (Insulin-like growth factor), Wnt, PARP (poly ADP ribose polymerase), HDAC
(histone deacetylase), AT (Janus tyrosine Kinase- Signal Transducer and Activator of
Transcription), Hedgehog, NOTCH, DNA Repair and Others’ intervention point (namely RET,
ALK, R051 and U81). These ention points have been selected because they can be
associated with an activation in a cancer. The rule that guides the choice of the invention in
this selection is to select the activation signals that can be blocked.
Optionally, in an alternative method, a subgroup of intervention points can be ed
among the above mentioned list of intervention points (i.e., a subgroup of 10, 12, 14, 16 or
18 intervention points). For instance, in a particular embodiment, a subgroup of intervention
points of interest includes the intervention points for which drugs are available. For instance,
such a subgroup may include or consist in the following group: Her, CDK4,6,
PLK/AURK/Kinesins, Angiogenesis, Immune tors PD1L and CTL14, PI3K, MET, MEK,
ERK, Anti-Apoptosis, FGF, mTOR, Ras/Raf, IGF/glycolysis, Wnt, PARP, and DNA .
In addition, for each intervention point, the ors carried out a ion of genes useful
for characterizing this intervention point. The list of genes is sed in Table 1 or 9.
In order to define the status of these intervention points in the tumor, several parameters
have to be defined based on the d list of genes that need to be investigated for each
patient.
In a first , expression levels of the genes of Table 1 or 9 are determined in the tumor
and normal samples. The sion levels are determined by measuring mRNA level. The
determination of the expression level variation for these mRNA is carried out by comparing
the expression levels in a tumor tissue and in the corresponding normal tissue. The gene
expression analysis allows the study of independent deregulations or deregulations due to
chromosomal aberrations. Indeed, the regulation of the transformational activity of genes is
complex and involves many levels of regulation: trans/cis transcription factors, promoters,
chromatin regulation, and the like. Generally, all lations (over-expression) are
ered with a ratio tumour/normal of at least 1.3. For each deregulated gene (i.e., gene
with a different mRNA expression when tumor and normal samples are compared), a fold
change and/or intensity of signal (proportional to the mRNA expression level) is determined.
Technologies that can be used comprise Northern analysis, mRNA or cDNA microarrays, RT-
PCT (in particular tative RT-PCR) and the like. Alternatively, the level of expression can
be determined with a ship comprising a set of primers or probes specific for the list of genes
of Table 1 or 9 or a set specific of genes of a subgroup of 10, 12, 14, 16 or 18 intervention
points as sed in Table 1 or 9. Expression levels ed from cancer and normal
samples may be normalized by using expression levels of proteins which are known to have
stable expression such as RPLPO (acidic ribosomal phosphoprotein PO), TBP (TATA box
binding protein), GAPDH (glyceraldehyde 3-phosphate dehydrogenase) or n.
It is important to note that the method according to the t invention is clearly distinct
from a method of global or whole analysis of gene sion. Even if some genes can be
added to the list of genes of Table 1 or 9, the gene expression is determined for less than
200, 250, or 300 genes.
In a second aspect, some genes of the list of genes of Table 1 and 9 are analyzed by
sequencing (partial or whole sequencing) or by hybridization for detecting the presence or
absence of mutations. For instance, exons of the genes of Table 1 or 9 can be sequenced by
any method available, preferably by a method of high throughput cing such as
|||umina or |on Torrent method or equivalent. Alternatively, only genes with known
activating mutation(s) can be analyzed. Such list of genes and mutations can change
depending on the considered cancer. In a particular ment, the genes of Table 10 can
be analyzed for the presence of mutations. More preferably, the method includes the
sequencing of p53, the most frequent d gene in solid tumors. For instance, the
method may include the determination of the presence/absence of mutations in the genes
p53, KRAS or NRAS rably KRAS), EGFR, EBBR2, P|K3CA and BRAF. Indeed, the presence
of mutation leading to a onal gain or loss has an important effect on biology of the
tumour without being always connected to variations of gene expression or of gene copy
. Many mutations are known to have a direct effect on the activity of a treatment by
inducing increased sensitivities or resistances. For example, the ons in the tyrosine
kinase domain of EGFR are often associated with sensitivity to the small molecules inhibiting
EGFR, the mutations in KRAS gene are associated with ance to the treatment by
monoclonal antibodies targeting EGFR. The mutational status can be determined by any
method known in the art, for ce by sequencing, microsequencing or hybridization. In
on, the gene mutations are listed in in www.sangerac.ungeneticsZCGPZcosmicz.
In a third aspect, the copy number variation of genes are defined for the tumor sample of
the subject. This is can be carried out by CGH (Comparative Genomic Hybridization)
which makes it possible to e the tumor DNA with the normal DNA of the same
individual to detect chromosomal aberrations, i.e. copy number variation such as
chromosomal losses or gains. This technology is well-known by the man skilled in the art. As
an illustration of this knowledge, the following reviews or reference books can be cited:
Davies et al. (2005, Chromosome ch, 13, 237-248). This technology is useful to identify
translocations. It can be easily carried out with frozen biopsies or tumor paraffin-included
material. CGH results are expressed as the ratios of copy numbers in the tumor material and
in normal tissue. A threshold of 0.5 is been acknowledged to describe a gain or a loss. More
this ratio is high, more the amplitude of the anomaly is important. Thus, an important
anomaly is likely to have a real impact at the biological level. In a preferred embodiment, a
fold change ofthe copy number variation is determined.
In a fourth , levels of miRNAs or microRNAs for the genes of Table 1 or 9 are
determined in the tumor and normal s. More preferably, the levels of 5 miRNAs for
each gene is determined. In a preferred embodiment, the miRNAs of Table 11 are analyzed.
The method for measuring miRNA are well-known in the art.
Then, a fold change Tumor versus Normal tissue is determined for the 5 miRNAs and a mean
fold change for each gene is calculated as the average of the fold changes ofthe 5 miRNAs.
Then, after the characterization step, the following parameters for the tumor of each
specific patient have been determined:
— A list of genes among the list of Table 1 or 9 with a deregulated expression with a
d fold-change.
— A list of mutated genes.
— Optionally, a list of genes having a Copy Number ion and a value (fold-
change) for this CNV. In a preferred embodiment, only the genes presenting an
amplification are taken into consideration.
— Optionally, a list of lated miRNA, in particular with an averaged fold
change based on the 5 miRNA fold-change.
In a first embodiment, the characterization method includes the gene expression analysis
and the mutated genes. In a second embodiment, the characterization method includes the
gene expression analysis, the mutated genes and the Copy Number Variation. In a third
embodiment, the characterization method includes the gene expression analysis, the
d genes and the miRNA analysis. In a fourth embodiment, the characterization
method includes the gene expression analysis, the mutated genes, the Copy Number
Variation and the miRNA analysis. The choice of the combination of criteria can be different
for each intervention point.
For instance, for some intervention points, the impact of miRNA has a major influence
whereas for other intervention points, miRNA has a minor influence. As shown in the
example section, for patients having NSCLC, miRNAs have a major impact on the
intervention points mTOR-AKT-PTEN, RAS, ERK, P|3K and Immune Modulators, whereas the
impact is minor for the intervention points Her, CDK4,6, Angiogenesis, MET, MEK, FGFR, RAF,
IGF-Warburg, and PARP. In on, for ts having NSCLC, the impact of CNV has been
determined as quite low.
From these ters, the method comprises that determination of the disturbed or
activated intervention points in the tumor of the patient and the ranking of them by
calculating a score for each intervention point.
Mathematical modeling/algorithm
The principles of the algorithm for calculating a score for each intervention point are the
followings:
1- The score is designed to ate with the likelihood that an intervention point is
(abnormally) activated or disturbed in the tumor, in particular in comparison to
the normal matched tissue of the same patient. It ranges from 1 to 20, the
t is the score, the most activated or disturbed is the pathway. In a
preferred ment, the score ranges from 1 to 10. However, the scale of the
score has no impact on the results.
2- The score may combine evidence from 4 data sources:
— Mutations;
— Mean fold change in gene ently expressed in the tumor vs. normal;
— Optionally, Mean fold change in expression of miRNA oftumor vs. normal; and,
— Optionally, Copy number variation.
Activating mutation and the score calculation
The different data sources may carry different weights in the score. Indeed, activating
mutation (e.g. K-RAS in the RAS pathway) may have decisive weight.
Then, in a first approach of the method, the maximal score is given to each intervention
point comprising a gene with an activating on. In a red embodiment, the
mutations associated with a l score are listed in Table 10. It may further include the
p53 mutations. For instance, if the score ranges from 0 to 10, the maximal score of 10 is
given to every intervention point comprising a gene with an activating mutation. In the
absence of a mutation, the score is based on an average of the mRNA mean fold changes,
optionally weighted with the level of expression of miRNAs and to a lesser extent CNV
abnormalities.
In a second ch, the rules of the first approach are carried out, but the score is the sum
of two scores, a first one based on mutation and a second one based on the arithmetic mean
of the mRNA mean fold changes. Preferably, the range/scale of the two scores is the same.
For instance, the two scores each range from 0 to 10.
In a third approach, the score is the sum of two scores, a first one based on mutation and a
second one based on the mRNA mean fold change. However, a different weight/score can
be given to mutations. In particular, instead of giving a score of 10 as soon as an activating
mutation is ed, a lower score can be given to the activating mutation, for instance a
score of 3. Accordingly, one mutation in a gene of an intervention point gives a score of 3,
two mutations a score of 6, three mutations a score of 9, more mutations the maximal score
of 10. In addition, ing on the impact of the activating mutations, a different weight
can be given. For instance, an activating mutation of KRAS gives a score of 10, whereas a
mutation with less functional impact will count for 3. Accordingly, mutations listed in Table
may have a higher weight, for instance may count 10.
ating the mean fold-change of differentially expressed genes:
The global expression pattern is used to ate a fold-change W of the expression of a
gene i in the tumor and in the matched normal tissue. This fold change can be referred as
mRNA TvN fold . It is calculated as the ratio of the sion of a gene in tumor on
the expression ofthe gene in a normal tissue.
For calculating the mean/average fold change of intervention point k, denoted as Ek, the fold
changes of differentially expressed genes with a fold change of at least 1.3 are used. In other
words, for each intervention point, an e fold-change of the genes iof the intervention
point k is calculated, trimming values with a threshold of 51.3.
Formally, we calculate Ek as the ing: let Mk denote the set of genes that belong to
intervention point k, and mk denote the subset of Mk that includes only differential
expressed genes with an absolute fold change 31.3. Ek is the average of the fold change of
the genes mk.
711,, = {aili E Mk and ngl 3:: 1.3}
We then calculate the mean expression level for all the genes in mk:
13,, = 3; wherein a? Emk
In other words, the fold change for a particular intervention point is the average or
etic mean of the fold changes of genes belonging to the intervention point as defined
in Table 1 or 9 and having a fold change T vs N of 1.3 or more.
In particular, in order to compare the fold changes of different intervention points, a relative
scoring, e.g., from 1 to 10, is generated based on the percentile calculation.
Combining mRNA and miRNA ements
To adjust for possible miRNA intervention in translation, the inventors propose to penalize
discordance between miRNA and its target mRNA. For each of the genes of Table 1 or 9 that
belong to the intervention points or a set thereof, the inventors determined the miRNAs
most likely to be involved in their regulation using Target scan {http://www.targetscan.org/},
ing the top 5 miRNAs for each gene. Table 11 provides a list of the top 5 miRNAs for
the genes of Table 1 or 9.
For each gene i, a mean miRNA fold-change can be calculated, which is denoted A,-, by
averaging the fold changes of the 5 miRNAs (or less if less than 5 miRNAs are identified) that
are most likely to target gene i. Then, for each gene, a mean miRNA TvN fold change is
determined.
Then, a corrected fold change of a gene of an intervention point is calculated by dividing the
mRNA fold change Tumor versus Normal of the gene (mRNA TvN fold change) by the mean
fold change for the miRNAs of the gene (mean miRNA TvN fold change). The ted fold
change of a gene is then used to calculate the fold change for a particular pathway by using
it in the calculation of the e fold changes of the genes ing to the pathway as
d in Table 1 or 9 and having a fold change T vs N of 1.3 or more. Based on the
corrected fold change of pathways, a corrected score, e.g., a score 1 to 10 is generated
based on percentiles.
Combining mRNA and CNV measurements
Only genes with amplification are taken into account. Preferably, genes with 2-fold or higher
amplification are ered as amplified. Then, a corrected fold change of a gene of an
intervention point is calculated by multiplying the mRNA fold change Tumor versus Normal
of the gene (mRNA TvN fold change) by the CNV fold change of the gene. The corrected fold
change of a gene is then used to calculate the fold change for a particular intervention point
by using it in the calculation of the average fold changes of the genes belonging to the
intervention point as defined in Table 1 or 9 and having a fold change T vs N of 1.3 or more.
Based on the corrected fold change of pathways, a corrected score, e.g., a score 1 to 10 is
generated based on percentiles.
Score calculation
To compare intervention , a score is given to each ention point, taking into
account mRNA expression and activating mutation. Optionally, 3 or 4 variables can be
considered: activating mutations, the Fold change of mRNAs in Tumor vs. Normal, the fold
change of miRNAs in Tumor vs. Normal and the copy number variation (amplifications,
deletions). In a preferred embodiment, the score is given to each intervention point, taking
into account ting mutations, mRNA expression, and miRNA sion. In a ular
ment, the miRNA is considered when calculating the score at least for the following
intervention points: mTOR-AKT-PTEN, RAS, ERK, P|3K and Immune Modulators.
To summarize, in a first aspect, the score for each pathway is calculated as follow:
1- If an ting mutation is detected in one gene of the intervention point, then
the score of the intervention point is the maximal score, e.g. 10 when scoring
from 1 to 10.
Otherwise, the score is calculated based on the average of the fold changes
tumor vs normal of the genes having an absolute fold change of at least 1.3 and
belonging to the list of genes of Table 1 or 9 for the considered intervention
point.
Optionally, if the miRNA level of the genes of Table 1 or 9 is measured, in
particular those of Table 11, a mean miRNA fold change for each gene is
calculated as the arithmetic mean of the fold change of 5 miRNAs of this gene.
Then a corrected mRNA fold change for the gene is calculated by dividing the
mRNA fold change Tumor versus Normal of the gene (mRNA TvN fold change) by
the mean fold change for the miRNAs of the gene (mean miRNA TvN fold change).
For calculating the mean of the mRNA tumor vs normal fold changes of the genes
of an intervention point, the corrected mRNA TvN fold change for the gene is
used.
Optionally, if the CNV of the genes of Table 1 or 9 (or some genes thereof) is
measured with 2-fold or higher amplification, then a corrected mRNA fold change
for the gene is calculated by multiplying the mRNA fold change Tumor versus
Normal of the gene (mRNA TvN fold ) by the CNV fold change for the gene.
For calculating the mean of the mRNA tumor vs normal fold changes of the genes
of an intervention point, the corrected mRNA TvN fold change for the gene is
used.
atively, it can also be chosen to attribute less weight to mutations, in particular when
considering the sequencing of all genes of Table 1 or 9. Accordingly, in a first alternative, the
score is the sum of the score due to mutational status and the score due to the mRNA
differential TvN expression. In a second alternative, in order to graduate the impact of the
mutations, a score of 3 is given by activating mutation. Then, for instance, the score of a
pathway is a score based on activating mutations with a maximal score of 10 added to a
score based on mRNA expression is calculated above with a l score of 10.
Accordingly, for each ention point, the score will be comprised between 0 and 20.
Based on the scores of the intervention points, the intervention points are ranked. The
pathway ranking can allow the one skilled in the art to select one or several combinations of
three activated or bed ention points, especially the combination of the three
most activated or disturbed intervention points according to the scores.
The pathways have been selected because drugs ic to each ention point are
already or soon available for treating a patient (see Table 1). Accordingly, based on the
combination of selected intervention points, a combination of drugs targeting these
intervention points can be selected and proposed for treating the t.
Therefore, the present invention relates to a method for selecting a combination of three
drugs useful for treating a patient having a cancer, wherein a group of three activated or
disturbed ention points are selected by the method of the present invention and a
drug is selected for each activated or disturbed intervention point, y providing a
combination of three drugs.
Prior any administration to a patient, the efficacy of the drugs combination can be tested ex
vivo. For instance, the combination can be tested on a model based on a biopsy of the tumor
from the patient. It can be tested on an animal model on which tumor cells from the tumor
has been grafted. Alternatively, it can be tested in a pre-clinical model called Metastatic Ex
Vivo Assay (MEVA). It is an in vitro 3D tissue culture through an anchorage independent
system.
Then, the present invention relates to a method of treatment of a patient having a cancer or
a method for selecting a combination of drugs for treating a patient having a cancer,
comprising:
— ing a tumor sample and an histologically matched normal tissue from the
patient;
— Characterizing the tumor sample in comparison to the normal sample as detailed
above;
— Calculating a score for each ention point as detailed above;
— Selecting three activated or disturbed intervention , preferably the three
most activated or disturbed intervention points;
— Selecting a combination of drugs targeting the three selected activated or
disturbed intervention points;
— Optionally, administrating to the patient the selected combination of drugs.
ally, the method of the present invention can provide several combinations of three
drugs. Indeed, in order to prevent any drug resistance, the combinations can be used
sequentially.
In addition, the present invention relates to a kit and the use of such a kit for classifying
intervention points according to their status and for selecting a combination of three drugs
chosen as targeting the most activated or bed ention points, wherein the kit
comprises means for measuring the mRNA expression level of the genes of Table 1 or 9. In
particular, such means can be primers and/or probes ic for each gene of Table 1 or 9.
Optionally, the kit may r comprise means for detecting the mutations in genes of Table
1 or 9. These means could be suitable for the whole sequencing of the genes of Table 1 or 9.
More preferably, the kit comprises means for detecting the mutations of Table 10. Means
can be probes specific of the nucleic acid sequence encoding a fragment including the
mutation. They can also be primers allowing the amplification and sequencing ofthe genes.
Optionally, the kit may further comprise means for determining the level of miRNA of genes
of Table 1 or 9, in particular those of Table 11. Finally, the kit may further comprise means
for ining the copy number variation ofthe genes of Table 1 or 9.
Finally, the present ion relates to drugs combinations of interest identified by the
method of the present invention. In a particular embodiment, the present invention relates
to a drugs combination including one drug targeting PDL1 or CTLA4 and two drugs selected
from the group consisting of an inhibitor of RAF, an inhibitor of Angiogenesis, an inhibitor of
MEK; an tor of MET and an inhibitor of CDK 4,6.
The main reason to define triple nt therapies as a combination of an
immunomodulator (anti PD1L or anti CTLA4) and two ed ies is to contain toxicity
of associations. Indeed, the main problem of combining targeted therapies might be the
additive toxicity. Whilst containing toxicity of dual combination was already demonstrated,
adding a third drug such as anti PD1L may contribute to an effective tolerated therapy, in
particular for metastatic NSCLC.
Accordingly, the present invention relates to a drugs combination for use in the treatment of
cancer, wherein the drugs combination is selected amoung the combinations disclosed in
Table 6, Table 7, Table 8.
Preferably, the drugs ation is the combination of three drugs. Optionally, it may
include additional drugs.
In a more specific ment, the present invention relates to a drugs combination
including a drug targeting PDL1, an inhibitor of RAF and a third targeted drug such as an
inhibitor of MEK6, an inhibitor of MET, an inhibitor of CDK4,6 or an inhibitor of angiogenesis.
Based on analysis of frequency of occurrence of activated entional points, and based
on is of trends of co-activation, the most important combinations are the following:
1. anti PD1L (e.g., AZ) + Pan RAF inhibitor (e.g., Takeda)* + MtorP|3K tor (e.g.,
Pfizer)
2. anti PD1L (e.g., AZ) + Pan RAF inhibitor (e.g., Takeda)* + angio- inhibitor (e.g., Pfizer)
3. anti PD1L (e.g., AZ) + Pan RAF inhibitor (e.g., Takeda)* + met inhibitor (e.g., Pfizer)
4. anti PD1L (e.g., AZ) + Pan RAF inhibitor (e.g., Takeda)* + CDK4,6 inhibitor (e.g., Pfizer)
these for combinations covers 51 % of patients with NSCLC as determined in the analysis of
the retrospective collection of 123 patients.
In on to these 4 combinations, the inventors determined that ing PD1L with
CTL14 fulfils the criteria of combining an immunomodulator with two others targeted drugs.
Four additional combinations can be oned, increasing the coverage of patients to 72%
. anti CTLA4 (e.g., AZ) + Pan RAF tor (e.g., Takeda)* + MtorP|3K inhibitor (e.g.,
Pfizer)
6. anti CTLA4 (e.g., AZ) + Pan RAF inhibitor (e.g., Takeda)* + angio- inhibitor (e.g., Pfizer)
7. anti CTLA4 (e.g., AZ) + Pan RAF tor (e.g., Takeda)* + met inhibitor (e.g., Pfizer)
8. anti CTLA4 (e.g., AZ) + Pan RAF tor (e.g., Takeda)* + CDK4,6 inhibitor (e.g.,
It is worthwile to mention that the Pan RAF inhibitor could be replaced with a MEK inhibitor
in most ofthe patients. This replacement generates 8 combinations:
9. anti PD1L (e.g., AZ) + MEK inhibitor + MtorP|3K dual inhibitor (e.g., Pfizer)
10. anti PD1L (e.g., AZ) + MEK inhibitor + angio-inhibitor (e.g., Pfizer or Takeda)
11. anti PD1L (e.g., AZ) + MEK inhibitor + met inhibitor (e.g., Pfizer)
12. anti PD1L (e.g., AZ) + MEK inhibitor + CDK,-6 inhibitor (e.g., Pfizer)
13. anti CTLA4 (e.g., AZ) + MEK inhibitor + MtorP|3K dual inhibitor (e.g., Pfizer)
14. anti CTLA4 (e.g., AZ) + MEK inhibitor + metinhibitor (e.g., Pfizer)
. anti CTLA4 (e.g., AZ) + MEK inhibitor + angio_inhibitor (e.g., Pfizer or Takeda)
16. anti CTLA4 (e.g., AZ) + MEK inhibitor + CDK4,6 inhibitor (e.g., Pfizer)
In a preferred embodiment, the above-mentioned drugs can be selected among those
disclosed in Table 1.
More preferably, the drugs combination is selected in the group consisting of
Medi-4736 (Astra Zeneca) + MLN2480 (Takeda) + PF-384 r)
Medi-4736 (Astra Zeneca) + MLN2480 (Takeda) + Axitinib (Pfizer) or
nib (Takeda)
Medi-4736 (Astra Zeneca) + MLN2480 (Takeda) + Crizotinib (Pfizer)
Medi-4736 (Astra Zeneca) + 0 (Takeda) + iclib (Pfizer)
Tremelimumab (Astra Zeneca) + MLN2480 a) + PF-384 (Pfizer)
Tremelimumab (Astra Zeneca) + 0 (Takeda) + Axitinib (Pfizer) or
Motesanib (Takeda)
Tremelimumab (Astra Zeneca) + MLN2480 a) + Crizotinib (Pfizer)
Tremelimumab (Astra Zeneca) + MLN2480 (Takeda) + Palbociclib (Pfizer)
Medi-4736 (Astra Zeneca) + Selumetinib (Astra Zeneca) + PF-384 (Pfizer)
Medi-4736 (Astra Zeneca) + tinib (Astra Zeneca) + Axitinib (Pfizer) or
Motesanib (Takeda)
Medi-4736 (Astra Zeneca) + Selumetinib (Astra Zeneca) + inib (Pfizer)
Medi-4736 (Astra Zeneca) + Selumetinib (Astra Zeneca) + iclib (Pfizer)
Tremelimumab (Astra Zeneca) + tinib (Astra Zeneca) + PF-384 (Pfizer)
Tremelimumab (Astra Zeneca) + Selumetinib (Astra Zeneca) + Crizotinib
(Pfizer)
Tremelimumab (Astra Zeneca) + Selumetinib (Astra Zeneca) + Axitinib (Pfizer)
or Motesanib (Takeda), and
Tremelimumab (Astra Zeneca) + Selumetinib v + iclib (Pfizer).
By a ”drugs ation”, it is ed to a pharmaceutical composition comprising the
drugs of the combination or to a kit or product comprising the drugs of the combination as a
combined preparation for simultaneous, separate or sequential use.
The present invention relates to
— a pharmaceutical composition comprising the drugs of the ation, and a
pharmaceutically acceptable carrier, in particular for use in the treatment of
cancer; and/or
— a product or kit containing the drugs of the combination, as a combined
ation for aneous, separate or sequential use, in particular in the
treatment of cancer; and/or
— a combined preparation which ses the drugs of the combination, for
simultaneous, separate or sequential use, in ular in the treatment of cancer;
and/or
— a pharmaceutical composition comprising the drugs of the combination for the
use in the treatment of cancer in combination with radiotherapy and/or or an
additional anti-tumoral agent; and/or
— the use of a pharmaceutical ition comprising the drugs of the combination
for the manufacture of a medicament for the treatment of cancer; and/or
— the use of a pharmaceutical composition comprising the drugs of the combination
for the manufacture of a medicament for the treatment of cancer in combination
with herapy, and/or or an additional anti-tumoral agent; and/or
— a method for treating a cancer in a t in need thereof, comprising
administering an effective amount of a pharmaceutical composition comprising
the drugs of the combination, and a pharmaceutically acceptable carrier; and/or
— a method for treating a cancer in a subject in need f, comprising
administering an effective amount ofthe drugs of the combination; and/or
— a method for treating a cancer in a subject in need thereof, comprising
administering an effective amount of a pharmaceutical ition sing
the drugs of the combination in combination with radiotherapy.
In a preferred embodiment, the cancer is a lung cancer, and more preferably a NSCLC.
The following r, describes material, methods and results presenting full investigation
of possibilities of combinations, based on magnitude and frequency of occurrence of
interventional points of activation as determined by the scoring system. In addition,
selection of combinations takes into account the trends of co-activation
EXAMPLES
Methods
Patients and Tissue Samples
The present study was organized by the CHEMORES initiative (Chemotherapy resistance
consortium), which is an EU funded (FP6) Integrated Project involving 19 academic s,
organizations for cancer research, and research-oriented biotechnology companies in 8
European countries.
Tissue samples from a cohort of 123 patients who underwent complete surgical ion at
the Institut Mutualiste Montsouris (Paris, France) between 30 January 2002 and 26 June
2006 were analysed. Clinical characteristics are given in Table 4 below. The median age of
patients was 63 years (range 41-85), 34 (28%) were female and 89 (72 %) were male. The
histopathology of all tumors was reviewed by the same ogist (Jde): 50 patients had
SCC, 57 AC, 13 LCC and 3 unclassified. Using the new 7th edition TNM staging 56 were stage
I, 25 stage II, 28 stage III and 4 stage IV. Adjuvant platinum based chemotherapy was
stered to 61 patients. Fifty-nine patients experienced a e. Two-year relapse-free
survival was 64%, and the median time to recurrence for the cohort was 5.2 years. After a
median follow up of 40 months (range 0-92) 36 patients had died and 23 patients were alive
with ence.
This study was performed using rozen tumor and nt normal lung tissue. Samples
were handled according to the Tumor Analysis Best Practices Working Group (Nat Rev Genet
2004; 52229-237). Haematoxylin and eosin d frozen sections, taken before and after
the cutting of slides for analysis, revealed a median cell content of 85% (an inter-quartile
range of 65% to 95%). All tissues were banked after written informed patient consent, and
the study was approved by the Ethics Committee of Institut Gustave Roussy (IGR). Genomic
investigations were performed at IGR, leader of the Genomic work-package of es
consortium, in the genomic center core facility certified |SO9001, labelled European
reference and training center for Agilent technologies. Analyses were performed at IGR and
Karolinska Institute, the leader of integrated analyzes work-package.
Table 2 - Characteristics of the patients in the study population
n=123 (100%)
Age median (range) 63 84.6)
Males n (%) 89 (72%)
Smoking Current 64 (52%)
Former 51 (42%)
Never 7 (6%)
Histology AC 57 (46%)
scc 50 (41%)
LCC 13 (11%)
Other 3 (3%)
Stage 1 56 (50%)
2 25 (22%)
3 28 (25%)
4 4 (4%)
Adjuvant Chemo (%) 61 (50%)
Data availability
The microarray data related to this study have been submitted to the Array Express data
repository at the European Bioinformatics Institute (http://www.ebi.ac.uk/arrayexpress/)
under the accession numbers E-MTAB-1132 (GE), E-MTAB-1133 (CGH) and E-MTAB-1134
(MIR).
Oligonucleotide aCGH
DNA samples were extracted from tissues using Qiagen QlAamp DNA Mini kit n,
Hilden, Germany). In each case, the normal tissue sample was used as the reference to its
corresponding tumor sample. DNA was restriction digested and controlled by Agilent
Bioanalyzer on DNA 7500 chips (Agilent Technologies, Santa Clara, CA, USA). The fragmented
nce and test DNA were labelled with Cy3-dUTP or TP, respectively, using
Agilent Genomic DNA Labelling Kit PLUS. Samples were purified using Microcon YM-30 filters
(Millipore, Billerica, MA). ization was carried out on t 244K arrays for 24 hours
at 65°C in a rotating oven (Robbins Scientific, Mountain View, CA) at 20rpm, followed by
appropriate g steps. Scanning was performed with an Agilent 62505C DNA
Microarray scanner using default parameters. Quantification of Cy5 and Cy3 signals from
scans was performed with Feature Extraction v10.5.1.1 (Agilent Technologies) using default
parameters.
CGH data processing and analysis
Resulting raw signals and log2 (ratio) profiles were normalized and centered according to
their dye composition (Cy5/Cy3) and local GC content. These profiles were segmented with
the Circular Binary Segmentation algorithm (Olshen et al. Biostatistics 2004 Oct;5(4):557-72)
through its implementation in the DNAcopy package for R v2.8.1 using default parameters.
DNA copy number imbalances were detected considering a minimum of 3 consecutive
probes and a minimal te amplitude threshold that was specific for each profile,
ingly with its internal noise. This specific internal noise was computed as one-fourth of
the median of the absolute log2 (ratio) distances across utive probes on the genome.
Of the 128 aCGH izations performed, 17 were discarded: 7 due to their clinical
annotations, 2 due to anomalies in their normal reference, and 8 due to the bad quality of
their profile, resulting in 111 usable profiles. All aCGH nates in this study are mapped
against the human genome as defined by the UCSC build hg18.
To assess the discovery of the genomic regions with differential ies between the AC,
LCC and SCC tions, ANOVA tests were med on the segmented aCGH dataset. To
account for multiple g, p-values were transformed to false ery rate (FDR)
(Benjamini et al. J Royal Statist Soc B 1995; 57:289-300).
Gene expression and microRNA microarray assay
The lysis of 40 to 50 frozen sections of 10 micron-thickness, cut from each NSCLC tissue
sample was done using a Polytron homogenizer (Ultraturrax, IMLAB, Lille, France). The RNA
extraction was performed with TR|zo|® Reagent protocol (Invitrogen, Carlsbad, CA, USA).
Total RNA was fied and qualified with Nanodrop ND-1000 spectrometer and
Bioanalyzer-2100 (Agilent Technologies).
For dual color Cy3 (normal s) and Cy5 (tumor samples) labelling, Agilent Fluorescent
Low Input Linear Amplification kit adapted for small amounts of total RNA (500 ng total RNA
per reaction) was used, followed by purification of labelled probes by Qiagen RNeasy Mini kit
and by a protocol provided by Agilent. Gene expression profiling was performed with dye-
swap, using dual-color 244K Human exon array from Agilent (custom design with the content
of the 44K Human genome plus 195000 probes, one for each exon as defined in refGene list
of UCSC build hg18 (http://genome.ucsc.edu/)). Hybridization was carried out for 17 hours at
65°C at 10 rpm, followed by washing steps. d microarray images were analyzed by
using Feature Extraction software version 10.5.1.1 (Agilent).
For the NA analysis, normal and tumor samples were hybridized on separate arrays.
Agilent miRNA Microarray System with miRNA complete labelling and hybridization kit was
used for Cy3 labelling. Briefly, isolated total RNAs were phorylated, labelled with pCp-
Cy3 and hybridized to Agilent 8x15K arrays for 20h at 55°C in a rotating oven (Robbins
Scientific) at 20 rpm. Slides were washed and scanned for gene expression using an Agilent
G2565C DNA microarray scanner using defaults parameters.
Gene mutations analysis
Sequencing was performed at IGR and at the Royal Institute of Technology (Stockholm,
Sweden). DNA was extracted with QIAamp DNA Mini Kit (Qiagen, Hilden, Germany). After
PCR amplification of target exons, sequencing reactions were carried out using the BigDye®
Terminator Cycle Sequencing Kit (Applied Biosystems, Forster City, CA). The primer
sequences are available on t. Sequencing reactions were run on a 48—capillary 3730
DNA Analyzer®. Sequence is and alignment was med with Sechape® software
(Applied Biosystems). All detected mutations were confirmed in at least one independent
PCR reaction. In all 123 samples, full coding sequences of exons including oncogenic
mutational hotspots were analyzed corresponding to: TP53 (NM_000546.4) exons 5-8; KRAS
(NM_004448.2) exons 2 and 3; EGFR (NM_005228.3) exons 18—21; P|K3CA (NM_006218.2)
exons 10 and 21,- BRAF (NM_004333.4) exon 15,- ERBBZ (NM_004448.2) exons 18, 20-24;
KDR 2253.1) exons 2, 26, 27 and 30,- and AKT1(NM_005163.2)exon 4.
xpression data processing and normalisation
All processing s used for gene sion analysis were performed on the median
signal from Agilent Feature Extraction raw data files using functions and packages collected
in the R Bioconductor project (Gentleman et al. Genome y, 5: R80) as well as custom
written routines.
For gene expression data, dye-swap arrays were first combined (by taking the average of
intensities) to obtained only one array per condition. This combination has the result of
2015/063263
ing the M values (log2ratios) on zero. Then, flagged spots as well as control spot were
d. ization was then performed using the izeWithinArrays function from
R package LIMMA (Smyth GK tical Applications in cs and Molecular Biology 2004,
vol3: N°1, article3).
For miRNA data, control spots were systematically removed, and flagged spots
(gIsFeatNonUnifOL and gIsSaturated columns from raw files) were considered as missing
values (”NA”). Array normalization was performed using the least-variant-set method (Suo et
al. RNA 2010 Dec,’ 16(12): 03).
Differential expression analyses of miRNA sion
To assess differentially-expressed miRNA, the inventors first estimated the fold changes and
standard errors between two groups of samples by fitting a linear model for each probe with
the lmFit function of LIMMA package in R. Then they applied an empirical Bayes smoothing
to the standard errors from the linear model previously computed with eBayes function.
Scoring/ ranking of activated interventional points
The algorithm
The mathematical ing and scoring system aims to give a score (1 to 10) based on
integration of omics data, cing, gene expression, miRNA and copy number variations
determined as differences between tumor and normal, individually for each patients.
SPRING scoring enables identification and ranking of activated pathways, and the overall
concept is that such activated pathways should be blocked with combined targeted
therapies.
The first mathematical model was established on the basis of a retrospective dataset from
123 patients with NSCLC for whom sequencing, Copy Number Variation, and tumor vs.
normal gene expression were available. Using these data, an algorithm that provides a score
of activation for each of the simplified pathway for the patient and factors in all of the
above-mentioned structural and functional results has been established. The principle of the
algorithm is disclosed in Figure 2.
Scoring is based on an intuitive algorithm that ates 4 types of genomic igations
of Tumor and Normal biopsies
1. ons: in V.1 the inventors used a very limited set of sequencing data, including
only the genes/mutations used currently in clinical care of NSCLC: EGFr, kRAS, BRAF,
PI3KCA, and HER2. Additionally they sequenced p53, the most frequent mutated
gene in lung (and all solid tumors).
a. When a mutation is detected, the algorithm assign the maximal score 10 in
the corresponding fied pathway.
2. Gene Expression: For each simplified pathway, mRNA steady state level in Tumor vs.
Normal is used to calculate a mean fold change of the pathway.
a. Values of individual Fold Change are trimmed at the threshold 1.3.
b. Values of individual mean fold s for each simplified y are
ranked in the retrospective set of data of 123 NSCLC, used as a calibrator.
c. As shown in 3 examples below, the range of Fold s is different from
one to other pathway. In order to compare them, the inventors ted a
relative scoring from 1 to 10 based on the percentile calculation.
3. miRNA expression: For each gene, the inventors selected top 5 matched miRNA from
TargetScan data base.
a. The fold changes T vs. N steady state level for each miRNA was used to
generate a mean fold change.
b. Fold change T vs. N for each gene was divided by the mean Fc T/N of the 5
corresponding miRNAs.
c. They generated then a corrected mean Fold change for each simplified
pathway.
d. They generated a corrected score 1 to 10 based on percentiles.
4. Copy Number Variation. When amplification is detected, the inventors multiplied the
value of the mRNA expression fold change for each gene by the value of the fold
change amplification. Then they generate the corrected mean fold change of
pathways and the percentiles score.
Table 3 summarises scores obtained for all patients of the 123 NSCLC, for a selection of
interventional points
P|3 ME ER FG mTO PAR JAK_STA CTLA
patient Histo Hre K | K X X ‘l'l 70 03? ‘1? PDL1
P T
AGG60071
6 AC 1 3 5 [\J J> (0 O1 01 CD co oo
ANO42052
0 AC 5 6 7 \l _\ O N (.0 [\3 \l 4> 01 10
ARC27051
7 SCC 9 4 1 _\ _\ (.0 8 2 3
\l N O) 3N moo
AZE45021
3 AC 8 10 9 J> \l \I 2 3 2 co co 10
BAR33112
3 SCC 8 7 10 _\ 0 CD .h (0 O) O) co \l 10
BAS26051
2 AC 10 1 3 _\ (.0 O1 _\ J> J> 01 c»
BAS26072
4 AC 5 10 8 (.0 CO CD N _\ CD 01 4> 10
BEM29112
9 SCC 5 1 1 CD O1 J> CD [\J 01 4> —\
BEN48070
7 SCC 1 1 2 .h 01 0) N (.0 CO c» [\3 10
BEN41052
9 LCC 7 3 9 01 O1 \l CD [\J _\ O _\ O 01
BER52043
0 AC 7 2 4
B|E410219 SCC 10 9 7 \IN O'l(.0 \l(.0 (OCT) \IN _\0‘l J>(.0 (ON
BOU48091
0 AC 9 3 6 N 01 O) \I 01 CD J> (.0
BOU29112
9 SCC 2 9 1 _\ O CO (.0 01 \I _\ _\ _\ O
BOU52011
1 AC 6 5 5 01 CD N G) \l _\ CD 01 10
BRO52112
7 AC 4 8 8 [\J \I (0 _\ [\J [\J 01 CD 10 10
BRZ47032
6 AC 10 9 9 oo _\ O _\ o CD _\ O N —\ 00 10
CAM52010
1 oo _\ o “3 \l .h N _\ _\ 10
CAP46021
LCC 1 4 1 (.0 _\ 0 [\J [\J 01 (.0 _\ O CO
4 AC 8 5 2 —\00 co .h _\ (.0 J> O1 (.0
8 LCC 8 5 5 CD [\J [\J _\ (.0 [\3 O1
CHA47071
8 LCC 4 6 10 co co \l CD _\ O (.0 \I [\3
CHE51122
AC 6 9 1 [\J 0) CD 3 9 3 CO _\ O
COU42020
1 AC 2 10 1 _\ O .h 01 _\ O _\ O
CRE42042
3 SCC 6 10 10 CD O) CD 10 10 9
DAM20041 SCC 2 10 9 \I N _\ O 3 6 10 (001 J>J> 10
UL) UL)
DAV32040
7 SCC 1 5 10 N N co _\ [\3 N CD
DEL33082
1 AC 7 8 7 5‘ 5‘ co HIEIIEHflflflflfllfliflflflflfllflfl-Hflflflfl (.0CDGD(.00 (04> _\ O N J> 10 10
DEP35112
1 SCC 5 9 6 oo c» c» _\ O [\3
DES58041
8 AC 10 6 3 \I co \1 0) _\ 0 10
06 AC 5 4 6 4> N co (.00) (7201 CD N
DHE32121
4 CD _\ O J> O1 _\ O CD
DOM5907
29 SCC 3 10 3 co N .h ODCO O1 ODCO J> _\ O 10
DUV33071
3 SCC 6 5 10 J> J> 0) N CO [\J O) _\ O 10
ECU52071
3 AC 3 10 8 A G) [\3 co _\ O 00 oo co
ED030081
2 SCC 7 5 2 (O G) N co co N 01 co
ELA54080
9 LCC 4 8 4 A A (.0 _\ 5 01 co _\ O 4>
ELB33072
8 AC 10 3 6 N N O1 [\3 —\ N c» 5‘
FER47103
1 AC 4 2 8 [\3 J> (.0 co co 4> c» \n
FER46123
0 SCC 3 5 7 6 5 7 6 6 5
6 7 10 _\50-: (.04
FLA49071
1 AC 5 5 8 1 2 2 5 8 1 _\ _\ O
1 AC 7 6 9 CD _\ O 01 J> J> _\ oo —\
FOR41072
7 SCC 6 7 4 _\ 0 (.0 _\ O (.0 N CD 4> c»
FRO44080
6 AC 2 2 3 01 CD (0 _\ (.0 CD 00 N
GAN35081
1 SCC 10 8 4 _\ CO CD CD CD _\ N 00
GAR41081
3 SCC 6 7 6 C00 c» _\ (Tl J> J> —\ 5‘
GAR45081
9 SCC 10 7 3 0) J> J> [\J J> 4> 5‘
6 AC 10 7 8 _\ O (.0 (0 oo _\ o 4> 4>
GEO27011
4 SCC 3 6 2 O1 _\ O O1 J> _\ _\5mm) c» N
G|D49022
4 AC 7 7 10 (.0 G) A O _\”o
G|L230901 SCC 3 1 2 CO(.0 NCD coco (7201
G|R22060
6 AC 9 1 3 N J> .h .h 00 co N
GOE19120
AC 10 4 7 O) —\ J> [\J N co co
GOM4502
27 SCC 9 4 6 _\ _\ O J> CD co co
GR025010
8 AC 10 7 10 8 4 8 10 6
—EIII___—n2
—m-2
—n-—————n2 CDJ>NCO
HAM64072
9 SCC 3 2 10 5 1 10 10 9 1 9 -fl 6
—-I5I____1 s N—\
HOU50110
6 AC CD _\ O 6
—--_7 NO‘ILO 0301 -l> _\\|_\¢o 4
—m-e
JAY440311 AC a
m —n10
—--m 9
KON381027 AC nu— 2
928 AC 4
LAM380228 \IcncoOo-nwoocoogco—x ooco©4>oo©0 —\—\LOO'ICOJ>—\CD AC “-—llcoco—\NNNOJAODCOO‘INN s J>CO—\COO'ICDO'IJ>—\CD
—-E_ 8
—-M_ 1o _\_\ OO
—fl-_ m 5
—-M_ _\Oco—xo 2
—\—\<.o —m- 2
"I!“ _\ 1
10 1
—fl-_0 2
LER460716 scc O1 co N—\ (no: cow coo-1 —n e oomco—xcogco—x
MAC46010
1 AC 7 _\ O) _\ —x 01 00 N [\3 4> 6
MAC38122
0 (DOO 4 4 4 [\J \n —‘ O oo 0-1 \l 0-1 6
MAR24091
1 (DOO 5 2 01 N —x c» \I —‘ O 0-: 01 6
MAR491 12
6 (DOO 7 J> (.0 4> N —‘ O co oo \l 6
MAR43072
6 AC co 0-1 c» 01 co N 6
MAR35050
7 (DOO 7 a: 5 10 co \l co —\ mm 6
MAR47032
2 LCC 3 5 7 2 -fl
4>o~1 0100 \IN \IO'I 6
_\0“ 0-101 4 GDCO
MER49031
8 AC In co 5‘ 6
NEG410311 AC 10 2 O) s
NI N270409 AC _\ 0 7 (.0 —m-2
PAN390607 AC (O (.0 .n—xwa‘oooo As—xcoa‘oo COCOO'INN J>—\-l>-l>l\)<.o wN!-l>\l(040)“) 1
PAQ470203 '_OO 1 01 \I 1
PEC481 1 13 AC 10 2 5 CD O1 N 2 J>
Other
PER401217 C - N —\ N —\ \I (0 —x .h -- 8 (.0
PER510713 AC [\J \l J> CD O) _\ J> O1 \l 8 2 6 7
906 SCC 5 1 9 1 1 7 7 2 6 4 2 4 1 5 2
—EE5 10"M2 2
RAM53032
1; all-- 7---83
—-nm———-m3 5
—-u—————m6 10
—mm10 10
—-l%l_____“5 3
6AI360426 Ac -fl_____“ 6 3
1 1
7 2
6113171101 Ac m—————— 6 7
7 5
TAI320613 Ac 7 1
2 3
TAT400301 Ac nu—————— 3 6
3 3
—--_____l-10 6
1 3
—--———mmn3 5
—n-m————m3 10
6
—mn7 10
—n-—————n3 2
In the next step, the inventors made the selection of all activated interventional points.
Scores 8, 9 and 10 were considered designating an important/high activation, s
scores 6 and 7 were considered designating medium tion. Scores <6 were considered
as designating non activated interventional points.
Table 4 shows the complexity of co-activation of interventional points. Each patient’s tumors
shows multiple activations, suggesting multiple possibilities of combinations. All 24
interventional points were analysed
High activation score: 8, 9 and 10 Medium activation score: 6 and 7
1:; 6s
-1; -:_1
-;:~
-:_1
-éNG' [PTKP RAF .PARP PDL1
GEF54 Ant AURK ANGI mTKP ModM TELOM CTLA
Her AGPT PI3K MEK FGF RAs -PDL1
1216 ia A o T TKT
KON38 Ant CDK ANGI mTKP PLAU TELO HDA
1027 iap 4_6 o T '
WO 93212
LAM , RCD
. IAAAG IGF‘ CDK SCDK
. RA HDA ANGI |GF_
AAAIII
Z|T4 AN _
. IGF_ HDA JAK_ CDK
AV'2
ER JAK NOT mTK
3091mm MEK FGF RAs RAE
K STAT PDL1 PI3K WNT HDAC
CH PT
AZE AN
CDK AGP TELO JAK_ CTLA
AAAI A r
BAS HED
2605 Her PARP GEH
12 G
BAS AN
4CD“ .
_ Am‘a TELO CM HDA
2607 AURKA GI MET PDL1 MEK RAS
~65 p M 4 C
24 O
BER mT HED
5204 Her FGF KP RAS GEH
T IGF 0G
3%; ME ANGI |GF_ JAK_ NOTC CTLA
Her AGPT WNT FGF RAS
K O War STAT H 4
BOU CT
AURK Ant'a. HDA DNA—
5201 AGF'T FGF LA Her MET RAF PDL1
A p C REP
11 4
BRO JAB;
5211 ED“: ME CTLA
ANGIQ STA
j K 4
27 T
BRZ AU .
4703 Her 23%": RK SNG' Anna DNA
PIBK MET MEK TFTKP PARP PDL1 CTLA4 FGF
26 _ p _REP
2805 Her PISK ERK AGPT WNT
CHE IAAAA IAAT
CDK ME mTKP TELO IGF_ DNA_ NOT Antla.
CDK ME Anna. mTKP M_M TELO JAK_
ME mTKP TELO HDA JAK_ DNA
RA IGF CTLA
W44 ANGIO MET RAF War— PDL1
s 4
0406
. IGF_W PA HDA DN/L CTLA 'AURK ANGI JAK_
FLA mT
TEL IGF_ HDA DNA_ PLAU
AS1307 ANGIO AGPT WNT PARP
OM War
-ANGIO Her CDK P|3K CTLA
WO 93212
4403 46 STAT REP
CTLA
4408 MET Antiap DNEA RAF
CDK mTKP DNA_ NOTC
4902 AMGIO MEK RAF WNT Her
S 4_6 T REP H
GI R HED
2206 Her ERK RAF AGPT MET GEH
06 0G
GOE AN HED
1912 Her AGPT GI RAS EDA GEH
05 O OG
CDK ,
, mTKP HDA JAIL CTLA
1008
GRY JAK_
TELO CTLA
STA RAS
G6U|
|GF_~ JAK_ NOT CDK HDA
ME HDA
Her PISK RAS RAF CTLA4
ME mTKP JAK_
5011 Her ANGIO EHO AGPT P|3K
STAT
IANGIOgGL3 HED
mTK lGF.
AGPT . GEH
4403 ANGIO Her AGPT AGPT
4209-1111310KRA mTKP IGF‘ JAK~ DNA CTLA
MET ERK
CDK ER Anna mTKP DNA_ CTLA AURK
4507 MET
4_6 K REP 4
CTLA
5605 .Amero PIBK MET RAF
PT 4
MAC F—a AURK TELO
ANGIO ERK WNT Her PARP PDL1
4601 M
MAR HED
AG |GF_
4307 Her ANGIO P|3K ERK AF PARP GEH PDL1
PT War
CDK AG mTKP JAK NOT
1103 PIBK MET MEK RAF
T IrGF_Wa
EDK ME JAK_ ANGI CTLA
2704 Her MEK RAF PDL1
_5 T TAT
ER HDA
3906 ANGID AGPT Her
K C
P|3 NOT
4811 Her ERK
JAK_
PDL1
STAT
CDK ME ANG' mTKP 'GF-
5303 Her PDL1 AGPT FGF WNT
ALE K O T War
R|T4 Au
CDK . HEDG
“'3 DNA NQTC CTLA
3110 Her RK PIBK MET ERK RAS RAF EHO
4~6 p
8 A G
CDK AG NOT AURK mTK TELO IGF Wa JAK
2042 ANGIO PIBK MET FGF RAs —
4‘6 PT CH PDLflA PT r STAT
S|K4
ANGIO é? MET ERK RAS {SE .RAF CTLA
PDL1
TA|3 HED
|GF_ DNA
s c
3 OG
TAT AN
Anna. mTKP TELO DNA CTLA CDK
4009 Her AURKA GI RAS
01 o l
IT IIIME JAK_ CTLA CDK Antla mTKP PAR DNA_
ARC AU HEDG
17 A HOG
BOU AU HED
CDK DNA NOTC
2911 Antiap RR. PIBK MET WNT PARP
REP Q'T'I-KMTELO HDAC
29 _ A HOG
DEP AU HEDG
21 ' A
. ME CDK HDA JAK_
”*8 RAF
.533;K AU
IGF_ HEDGE DNA_
M59 PISK ERK FGF .IAELO WNT HDAC
War HOG REP
0729 — A
HEDG -
GAN . K AUR TELO DNA NOTC
Antlap Her PI3K PARP EH0 MEK FGF
3508 4‘ KA
GEO HED
ME “DA JAK— DNA_ NOTC CDK |GF_Wa
2701 Antiap AURKA ERK RAs GEH WNT
T c STAT
14 OS
HAM AN
ASP TELO
6407 Antiap AURKA GI MEK ERK FGF RAS 1m
T M :5;—
29 0
P13 mTKP TELO
3206 Antiap Her MET MEK FGF RAF RAS
K $111
LEF - AN
lGF. DNA_
HDAC
War :EgGE REP
9%: ANGI mTKP HDA DNA_
FGF PARP
REP New
11 . A
LEN HED
mTKP TELO DNA_ NOT
FGF GEH
IGF NOT
3‘: War
mTKP
ERK RAF PARP
R ATDNA_REP
REC CDK K AGF’
Antiap PIEK
5907 46 4 T
SAU HED
TELO
FGF RA GEH PARP
OG “0T
ER IGF TELO NOT
3008 Antiap ANGIO RAF PDL1
K War
v1L3 AN HED
1030 Antiap AUBKA G! PISK MET
9 0 0G
BAR AN HED
AGP Antia mTKP TELO
3311 Her AURKA GI PI3K RAB RAF HDAC GEH
B:E1M MKS ER Antia ONT CTLA
PI3K FGF
TAT CH 4
BEN JAK_
4807 PDL1 STA
4105 ANGIO AGPT RAS RAF
A C
B1E4 Au
IAntia (I);I}: DNA CTLA ANGI mTKP
TELO IGF
M War
01 _
CAP HED
4602 AUBKA MET .Am GEH AGPT
18113
OG
IGF_ CTLA
mTKP CTLA CDK G|F_ DNAR
ANGIO AGPT ERK
CRE HEDG
CDK AG mTKP TELO |_GF NOT
4204 ANG10 MET FGF EHO PDL1 CTLA4
4_6 PT T
CDK AG JAK_ NOT CTLA mTK
404 RAS RAF
STAT
DAV HED
3204 ANGIO Ant IGF NOT
AURKA FGF 1 :24 MET .PARP PDL1
lap War CH ETLA
07 0G
-ANGIO AGPT Anna TKP RAF PARP DNA NOTC PDL1
3307 T War
E3DO
PAR TELO NOT CTLA
I152LA HED
5408 53%" NOT
FGF RAF LEE HDA
WNT GEH PDL1
s ar
09 _
FER AN
4612 AGPT EEEGEW'PBK PI3K MEK WNT HDAC
'AURKAFOR JAK HED
PISK ISTA NOT .T.4_6CDK
GEH ERK ETTK .TELOM PARP
G7AR OG
TE HED HED
4108 AURKA PTBK LO WNT RARR GEH GEH ggfi‘mNOT PDL1 .2323K ANGIO AGPT
13 M 06
GAR Ant HED
4508 Her PISK iap 5% SEQC”OT HDA
WNT RARR GEH
19 AlumcCTLACDK opt OG
GI L2 HEDG
IGFJN HD mTKP TELO JAK_ DNARE
AU - HED
“ma TELO 'GF~ HDA NOT ANG' ME
GOM45 Her RK AGRT PISK FGF RARR GEH
p M War C CH
0227 A
Au HED
mTKP TELO ”DA DNA NOT CDK
HAR331 Her RK P13K MEK WNT RARR GEH
T M c RER CH GINO
217 A 06
Anti JAK- TELO DNA
|SA3009 ERK RAS 2E3 ERK PARP
3p STAT M REP
17 06
_3T AGPT P|3K MEK ERK RAF PDL1
31 AT
.PIBKAG mTKP CTLA NOT
MET MEK
16 T PDL1-FGF RAS
O CH
$131: .
, Anna
LAN041 Her K AURKA MET MEK FGF RARR
p 2m: RAF Km {SE a’ :0C
130 4_6
JAK- DNA CTLA RA
LAN510 Her K AURKA PIBK MEK FGF RAS GEH PDL1
p 6 AT RER 4 F
426 46 013
LEJ501 JAK_ AG Antia
1 15 STAT
LEM351 Her. D mTK TELO IGF HDA DNA
PARP .06GEH P|3K ERK
M War REP
LER460 gNG'RA JAK
CTLA4 RAF — GEH PDL1
S STAT
716 OG
MAR240 I.RAF ME TELO |GF_ DNA NOT
M W” .35;H
Au HED
cm“ Am'a. mTKP DNA CTLA TEL
WWEW:WRW...EMIMMAR491 RK AGPT FGF WNT GEH Her RAS
p T RER 4 OM
126 06
HDA JAK_ DNA CTIA AURK ANGI Antla. mTKP TEL
CDK Antia mTKP TELO HDA JAK_ DNA CTLA
MAT230 RK RISK PDL1
T STAT REP
CDK Anna. mTKP TELO HDA DNA NUT
PAQ470 RK PM WNT P|3K PARP
p REP CH
lGF HED
PIQ340 HDAC MEK ERK GEH PDL1
CDK P13 TELD lGF HDA DNA NOT
RAB330 Antiap RAS — WNT PARP GEH Her
M war C
06 REP CH
AU . CD
005 A 4_6
ar
ANGI DNA NOT mTKP HDA
SUT470 Antiap WNT PARF’ GEH MEK PDL1
REP CH T C
Anti HDA NOT CDK
TAR290 ERK FGF PARP GEH
ANG' TELO NOT
THU220 AGPT IGF_War PDL1 FGF WNT PARP GEH
8 o M CH
630 - OG
T|L4202 ER JAK_ST CTLA |GF_ HD
AGPT PI3K .MEK FGF RAF
28 Hr:-- PDL1 4 War PARP-
36K PAR gm
W SE” 3.2: [Am W
VAL271 JAK_ Antia mTKP |GF_ NOT
FGF .TELOM WNT PARP
009 STAT PDL1-ERK popt T War
. HED
AURK Pl3 Antla TELO HDA JAK‘ DNA NOT PDL
In a preferred embodiment, the frequence of activation of inteventional points (score>5),
enabling determination of the most rationale combinations is the following
Table 5. Trends of cooactivation of entional points
CTL PD me mT pi3 E}? m AkAur cdk4 HRE Aing FFG PA RasF/R IG DNAR mtorK/PI Histo
patient
61 63 54 59 55 57 51 55 56 47 47 88 44 56 83 123
Table 6. Selection of most frequent combinations taking into account trends of coactivation.
For each of the first and second drug number of patients (upper case) and % (lower case) are
showed. For each of the third drug number ents out of 123 and % are shown.
Firstdru NBI% Seconddru NBI% %
“SW“
“SR”
RAS/RAF 19
PD1 L N C) 16
FGF 15
PARP 13
RAS/RAF 28
CTLA4 20
DNARepair 19
CDK4,6 17
ANGIO 17
mTor/PI3K
AURKA 16
IGF 15
FGF 15
MET 13
PARP 12
CTLA4 24
PD1 L 23
mTor/PI3K 23
CDK4,6 15
ANGIO 15
RAS/RAF
IGF 15
AURKA 13
FGF 13
DNARepair 12
parp 9
RAS/RAF 26
AURKA 26
DNARepair 26
CTLA4 24
parp 21
mTor/PI3K
FGF 19
MET 18
PD1 L 17
ANGIO 16
IGF 12
CTLA4 26
mTor/PI3K 22
PD1 L 18
ANGIO 17
MEK 15
RAS/RAF
AURKA 14
FGF 14
DNARepair 12
IGF 11
PARP 10
I3K 22
PD1 L 20
MET 16
MEK 15
AURKA 15
RAS/RAF
IGF 14
CDK4,6 13
FGF 12
DNARepair AA_\_\_\_\NNN_\_\_\_\_\_\MNN004NNNNNNQJQJQ)AAA—\AAANNNAAAANNNNNQJAA #CTIO‘JNCOCOO-PNNOOCTINNCO—‘N\INCJ‘IC)ANWO‘JCONMN—‘CNO‘JO‘JCOCOCOCOCOCOCNO‘JCOCOO—‘Awm#O‘Jw 11
PARP \l 6
Table 7 summarizes the mostfrequent triple ations
mum-m“
“um—n
————”-m-
————”-m-
————”-m-
______n
——————m-
"mm-
___“_m-
"mm-
"mm-
——————m-
Table 8. Summarizes the most ent combinations involving and immunomodulator
mum-m“
____-_-_
——————m-
mum-m“
______n
——————n
____n
——————m-
"mm-
——————m-
TABLE 9: Detailed List of genes
Symbol Genel
Pathwa D
EGF 1950 epidermal growth factor NM_001963
TGFA 7039 transforming growth factor, alpha 236
AREG 374
EREG 2069
HBEGF 1839
BTC 685
NRG1 3084
NM_004495
NRG2 9542
83H 29; NM_013982
NRG4 14595
EGFR 1956
NM_201282;
NM_005228
ERBB2 2064 v-erb-b2 avian erythroblastic leukemia viral ne NM_001005862;
homo|00 2 AB025286
ERBB3 2065 v-erb-b2 avian erythroblastic leukemia viral oncogene NM_001982;
homo|00 3 NM_001005915
ERBB4 2066
homolo. 4
CDK4 44$83m—xco cyclin-dependent kinase 4 NM_000075
CDK6 cyclin-dependent kinase 6 NM_001259
CCND1 cyclin D1 NM_053056
CCND2 894 cyclin D2 759
9‘l7MGO CCND3 896 cyclin D3 NM_001760
, 1029
NM_000077
CDKN2B 1030 NM_004936
CCNE1 898 cyclin E1 NM_001238
CCNE2 9134 cyclin E2 NM_057749
RB1 5925 retinoblastoma 1 321
polo-like kinase 1 NM_005030
M'Id
sugsaum aurora kinase A NM_198433
MHnV bora, aurora kinase A activator NM_024808
ILK 3611 integrin-linked kinase NM_001014795
/ K|F11 3832 kinesin family member 11 NM_004523
SISHNHSOISNV VEGFA 7422 vascular endothelial growth factor A NM_001025370;
025366
VEGFB 7423 vascular endothelial growth factor B NM_003377
VEGFC 7424 vascular endothelial growth factor C NM_005429
VEGFD 2277 c-fos induced growth factor (vascular endothelial growth NM_004469
factor D
FLT1 2321 fms-related tyrosine kinase 1 NM_001160031;
NM_002019
KDR 3791 kinase insert domain receptor (a type I” receptor tyrosine NM_002253
kinase
FLT4 2324
68; NM_002020
PDGFA 5154
NM_033023
PDGFB platelet-derived growth factor beta polypeptide NM_002608
PDGFRA platelet-derived growth factor receptor, alpha polypeptide NM 006206
PDGFRB platelet-derived growth factor receptor, beta polypeptide NM_002609
Kit 3815
homo|00 NM_001093772
thrombospondin 1 NM_003246
transforming growth factor, beta 1 NM_000660
SNIlHIOdOISNV angiopoietin 1 NM_001146
angiopoietin 2 NM_001147
angiopoietin-like 1 NM_004673
angiopoietin 4 NM 015985
T|E1 7075 tyrosine kinase with immunoglobulin-like and EGF-like NM_005424
domains 1
TEK 7010 TEK tyrosine , endothelial NM_000459
CD274 or 29126
PDL1 pr0orammed cell death lioand 1
J012|np0w 'OanNINI PDCD1LG2 80380 programmed cell death 1 ligand 2 NM_025239
PDCD1 5133 programmed cell death 1 NM_005018
CTLA4 1493 cytotoxic T-lymphocyte-associated n 4 NM_005214
LAG3 3902 lymphocyte-activation gene 3 NM_002286
P|K3CA 5290 phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic NM_006218
subunit aloha
P|K3CB 5291 atidylinositol-4,5-bisphosphate 3-kinase, catalytic 219
subunit beta
P|K3CD 5293 phosphatidylinositol-4,5-bisphosphate 3-kinase, tic, NM_005026
catal tic subunit delta
P|K3CG 5294 phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic 649
subunit oamma
P|3K B 5287 phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic 646;
subunit type 2 beta ENST000003671
PRKCB 5579 protein kinase C, beta
PRKCA 5578 protein kinase C, alpha
P|K3R1 5295 phosphoinositidekinase, regulatory subunit 1 (alpha)
P|K3R2 5296 phosphoinositidekinase, regulatory subunit 2 (beta)
P|K3R3 8503 oinositidekinase, regulatory t 3 (gamma)
HGF 3082 hepatocyte growth factor (hepapoietin A; scatter factor) NM_001010934;
NM_001010931
MET 4233 met proto-oncogene
AXL 558 AXL receptor tyrosine kinase
MST1 R 4486 hage stimulating 1 receptor (c-met-related tyrosine NM_002447
kinase
2015/063263
MAP2K1 5604 mitogen-activated protein kinase kinase 1, E3 ubiquitin NM_002755
orotein Iioase
MAP2K2 5605 n-activated protein kinase kinase 2 NM_030662
MAP2K3 5606 mitogen-activated n kinase kinase 3 NM_145109;
ENST00000534743
MEK MAP2K4 mitogen-activated protein kinase kinase 4
MAP3K1 4214 n-activated protein kinase kinase kinase 1
MAP3K2 10746 mitogen-activated protein kinase kinase kinase 2
MAP3K3 4215 mitogen-activated protein kinase kinase kinase 3
MAP3K4 4216 mitogen-activated protein kinase kinase kinase 4 NM_005922;
NM_006724
mitogen-activated protein kinase 3
mitogen-activated protein kinase 1
kinase suppressor of ras 1
MAPK11 5600 mitogen-activated protein kinase 11
BCL2 596 B-cell CLL/lymphoma 2 NM:000633;
SlSOldOdV NM_000657
'llNV BCL2L1 598 BCL2-Iike1
BIRC5 332 baculoviral|APrepeatcontaining5
XIAP 331 X-Iinked inhibitorof apoptosis
BAK1 578 BCL2-antagonist/killer 1
FGF1 2246 fibroblast growth factor 1 (acidic) NM_000800;
NR_026696
fibroblast growth factor 2 (basic)
fibroblast growth factor 3
fibroblast growth factor 4
FGF5 2250 fibroblast growth factor 5 NM_004464;
FGF6 2251 fibroblast growth factor 6
FGF7 2252 fibroblast growth factor 7
FGF8 2253 fibroblast growth factor 8 gen-induced)
fibroblast growth factor 9
FGF fibroblast growth factor 10
fibroblast growth factor 11
fibroblast growth factor 12
fibroblast growth factor 13
FGF14 2259 fibroblast growth factor 14
FGFR1 2260 fibroblast growth factor receptor 1 ENST00000496296;
NM_023110;
NM_001174066
FGFR2 2263 fibroblast growth factor or 2 ENST00000359354;
fibroblast growth factor receptor 3
FGFR4 2264 fibroblast growth factor receptor 4
2475 mechanistictargetofrapamycin(serine/threonine kinase) NM_004958
mTOR - AKT1 v-akt murine thymoma viral oncogene homolog 1 NM_005163
AKTAKT2
v-akt murine a viral oncogene homolog 2 NM_001626
PTEN-
PTEN 5728 phosphatase and tensin homolog NM_000314
TSC1 7248 tuberous sclerosis 1 NM_000368;
Sicieinpow ENST00000403810
NM_001077183
serine/threonine kinase 11 NM_000455
ldMllN pim-1 oncogene NM_002648
pim-2 oncogene NM_006875
pim-3 oncogene NM_001001852
””3336“
NM_004985
NRAS 4893 neuroblastoma RAS viral (v-ras) oncogene homolog NM_002524
HRAS 3265 Harvey rat a viral oncogene homolog NM_005343
RAF RAF1 5894 v-raf-1 murine leukemia viral oncogene homolog 1 NM 002880
v-raf murine sarcoma viral oncogene homolog B NM_004333
telomerase reverse riptase NM_198253
HSVHHINO'IEL telomerase RNA component NR_001566
telomerase-associated protein 1 NM_007110
”ll—001017963;
NM_005348
dyskeratosis ita 1, dyskerin NM_001363
prostaglandin E synthase 3 NM_006601
insulin-like growth factor1 omedin C) NM_000618
insulin-like growth factor 2 (somatomedin A) NM_000612
:IEJI
insulin-like growth factor1 receptor 875
5mqu insulin-like growth factor 2 receptor NM_000876
INSR 3643 insulin receptor NM_000208
|RS1 3667 insulin receptorsubstrate 1 NM_005544
PKM 5315 pyruvate kinase, muscle NM 001206796 1
cadherin 1, type 1, erin (epithelial) NM_004360
catenin (cadherin-associated protein), alpha 1, 102 kDa NM_001903
catenin (cadherin-associated protein), beta 1, 88 kDa NM_001904;
098210
wingless-type MMTV integration site family, member 1 NM_005430
WNT FZD1 8321 frizzled class receptor 1 NM_003505
wingless-type MMTV integration site family, member 5A NM_003392
ss-type MMTV integration site , member 5B NM_030775
frizzled class receptor 5 NM_003468
WNT inhibitory factor1 191
dickkohWNT signaling pathway tor 1 NM_012242
PARP1 142 poly (ADP-ribose) polymerase 1 NM_001618;
ENST00000366790
breast cancer 1, early onset NM_007300
XRCC1 7515 X-ray repaircomplementing defective repairin Chinese NM_006297
PARP hamster cells 1
RAD54L 8438 RAD54-like (S. cerevisiae) NM_003579
RAD54B 25788 RAD54 homolog B (S. cerevisiae) 415;
NM_001205262
ATM 472 ataxia telangiectasia mutated NM_000051;
ENST00000389511
ATR 545 ataxia telangiectasia and Rad3 related NM_001184
checkpoint kinase1 NM_001114121
NM_001005735
WEE1 G2 checkpoint kinase NM_003390
histone ylase 1 NM_004964
histone deacetylase 2 NM_001527
HDAC histone deacetylase 3 NM_003883
e deacetylase 4 037
histone ylase 5 NM 001015053
JAK1 3716 Janus kinase 1 NM_002227
JAK2 3717 Janus kinase 2 NM_004972
E signal transducerand activator of transcription 1, 91 kDa NM_139266
'g signal transducerand activator of transcription 2, 113 kDa NM_005419
:3. signal transducer and activator of transcription 3 (acute- NM_213662
phase response factor
ssor of cytokine signaling 1 NM_003745
SHH 6469 sonic hedgehog NM_000193
ENST00000375290
g SMO 6608 smoothened, frizzled class receptor NM_005631
fl serine/threonine kinase 36 NM 015690
é protein kinase, cAMP-dependent, tic, alpha 730
NM_001178133
GLI family zinc finger 1 NM_005269
excision repair cross-complementation group 1 NM_202001
RAD52 g (s. cerevisiae) NM_134424;
ENST00000545967
g; hamster cells 4
g RAD51 recombinase NM_002875
2—; breast cancer 1, early onset NM_007300
re ulated 8
NEDD8 activating enzyme E1 subunit 1 NM 001018159
notch 1 NM_017617
ADAM metallopeptidase domain 17 NM_003183
ENST00000394157
g nicastrin NM_015331
' JAG1 182 jagged 1 NM_000214
NM_015908;
NM_001128854
NM_001077628
2015/063263
R081 6098 c-ros oncogene 1 , receptor tyrosine kinase ENSTOOOOO403284
; NM_002944
anaplastic lymphoma receptor tyrosine kinase 304
RET 5979 ret oncogene NM_020630;
NM_020975
UBA1 7317 ubiquitin-like modifier activating enzyme 1 334
TABLE 10 : List of genes mutations
BRAF
c.1799 T>W p.Va|6OOG|u V600E
c. 1798 G>R
p.Val600LyS V600K
c.1799 T>W
c.1799 T>W c.1SOOG>R p.Va|6OOG|u V600E
EGFR
Nucleotide Protein IEffect on EGFR
inhibitors
c.2156G>C p.Gly719Ala G719A ility
c.2155 G>K p.Gly719CyS G719C Sensibility
c.2117 T>Y p.||e706Thr I706T Sensibility
c.2125 G>R p.G|u709LyS E709K Sensibility
c.2126 A>M p.G|u709AIa E709A Sensibility
c.2174 C>Y p.Thr725Met T725M Sensibility
c.2165C>M p.A|a7ZZG|u A722E Sensibility
Delet'on E746" 'l'ty
c.2235_2249 del p.G|u746_Ala750del
A750
Delet'on E746" sens'b'l'ty
c.2236_2250 del p.G|u746_Ala750del
A750
Delet'on L747" 'l'ty
c.2240_2254del p.Leu747_Thr751del
T751
Deletion L747- Sensibility
c.2240_2257 del p.Leu747_Pro753delinSSer P753
Insertion S
Deletion E746- Sensibility
c.2237_2251de| p.G|u746_Thr751de|inSA|a T751
Insertion A
Deletion L747- Sensibility
c.2239_2248de|inSC p.Leu747_Ala750delinSPro A750
Insertion P
Deletion L747- Sensibility
c.2239_2251de|inSC p.Leu747_Thr751delinSPro T751
Insertion P
Deletion E746- Sensibility
c.2237_2255 delinST p.G|u746_Ser752delinSVal S752
Insertion V
c.2214_2231dup 40_LyS745dup Duplication I740- Sensibility
K745
Deletion S752- Sensibility
C.2254_2277 del p.Ser752_|le759del
I759
K745-E746 Sensibility
c.2219_2236dup p. _Glu746insValProValAla||eLys
Insertion VPVAIK
c.2277 c>s p.||e759 Met I759M ility
Deletion L747- Sensibility
C.2239_2256de|insCAA p.Leu747_Ser752delinsGln S752
Insertion Q
c.2369C>Y p.Thr790Met T790M Resistance
C.2317_2318insACC 73dup Duplication H773 Resistance
773 Resistance
c.2317_2318in512 p.Pro772_His773insLeuGlyAsnPro
insertion LGNP
Duplication P772- Resistance
c.2315_2326dup p.Pro772_Cys775dup
C775
Duplication A767- Resistance
_2308 clup 67_Va|769dup
V769
Duplication S768- Resistance
c.2303_2311 clup p.Ser768_Asp770dup
D770
Duplication S768- Resistance
c.2303_2311dup p.Ser768_Asp770dup
D770
C.2335G>T p.Gly779Cys G779C Resistance
c.2573 T>K p.Leu858Arg L858R Sensibility
c.2582 T>W p.Leu86lGln L861Q ility
KRAS-NRAS
Nucleotide Protein
c.34 G>K p.Gly12Cys 612C
c.35 G>R p.Gly12Asp GlZD
c.35 G>K p.Gly12Val GlZV
c.35 G>S p.Gly12Ala 612A
c.34 G>R p.Gly12Ser GlZS
c.34 G>S p.Gly12Arg 612R
c.38 G>R p.Gly13Asp 613D
c.37 G>K 3Cys 613C
c.182 A>W p.G|n61Leu Q61L
c.182 A>R p.G|n61Arg Q61R
c.183 A>M p.G|n61His Q61H
c.176 C>S p.A|a59Gly A59G
c.175 G>R p.A|a59Thr A59T
c.176 C>M p.A|a59Glu A59E
ERBBZ
c.2313_2324dup p.Tyr772_Ala775dup Duplication Y772-A775
c.2318_2319insGATGGCATACGT p.Tyr772_Ala775dup Duplication Y772-A775
Deletion G776
c.2326_2327|nsTGT. p.Gly776delinsVaICys.
c2331_2339dup p.G|y778_Pro780dup Duplication G778-P780
FUK3CA
Nucleotide Protein
c.1624 G>R p.G|u542Lys E542K
c.1633G>R p.G|u545Lys E545K
c.3140A>R p.Hile47Arg H1047R
c.3140A>W p.Hile47Leu H1047L
c.2959 G>R p.Ala987Thr A987T
c.30526>A p.Asp1018Asn D1018N
c.3080 C>Y p.Ala1027Val A1027V
c.3131A>R p.Asn1044Ser N1044S
TABLE 11 : List of miRNA
Symbol
Pathwa
EGF 1950 hsa-miR-4673; hsa-miR5p; hsa-miR-647 ; hsa-miR5p ; hsa-miR5p
TGFA 7039 hsa-miR-3147; hsa-miR-1178; hsa-miR-626; hsa-miR-148a; hsa-miR-1182
AREG 374 hsa-miR-517a ; hsa-miR-34c-5p ; hsa-miR3p ; hsa-miR5p ; hsa-miR-
517b
EREG 2069 hsa-miR5p ; hsa-miR5p ; hsa-miR-130a ; hsa-miR-3661 ; hsa-miR-192
HBEGF 1839 hsa-miR-4736; hsa-miR5p; hsa-miR-4710; hsa-miR5p; hsa-miR-1271
BTC CD0) O1 hsa-miR3p; hsa-miR-1200; hsa-miR5p; hsa-miR-934; hsa-miR-488
NRG1 3084 hsa-miR-4632; hsa-miR-1203; hsa-miR-552; hsa-miR-4736; hsa-miR-183
HEIH NRG2 9542 hsa-miR-3196; hsa-miR-3934; hsa-miR5p; R5p; hsa-miR5p
NRG4 145957 hsa-miR-608; hsa-miR-1301; hsa-miR3p; hsa-miR-516b; hsa-miR-3681;
EGFR 1956 hsa-miR-4417; hsa-miR-608; hsa-miR3p; hsa-miR3p; hsa-miR-7;
ERBB2 2064 hsa-miR3p; hsa-miR5p; R-1972; hsa-miR-4533; hsa-miR-1296;
ERBB3 2065 R-3199; hsa-miR-4505; hsa-miR-1287; hsa-miR-3153; hsa-miR-4290;
ERBB4 2066 hsa-miR-4469; hsa-miR-193a-3p; hsa-miR-642a; hsa-miR-3907; hsa-miR3p;
CDK4 1019 hsa-miR5p; hsa-miR-198; hsa-miR5p; hsa-miR-765; hsa-miR-4280;
CDK6 1021 R-3680; R3p; hsa-miR-621; hsa-miR-644; hsa-miR-4252;
CCND1 R3p; hsa-miR-3170; hsa-miR-1193; hsa-miR3p; hsa-miR-4632;
CCND2 894 R-1468; R-103b; hsa-miR-1205; hsa-miR3p; hsa-miR-4718;
9‘VMGO CCND3 896 hsa-miR5p; hsa-miR-4739; hsa-miR-138; hsa-miR5p; hsa-miR-3154;
CDKN2A, 1029 hsa-miR-663b; hsa-miR-675; hsa-miR-663; hsa-miR-1291; hsa-miR-621;
CDKN2B 1030 hsa-miR-4308; hsa-miR-718; hsa-miR-1914; hsa-miR-451; hsa-miR-346;
CCNE1 898 hsa-miR-16; hsa-miR-874; hsa-miR-146b-3p; hsa-miR-4524; hsa-miR-3190;
CCNE2 9134 hsa-miR-449a; hsa-miR-370; hsa-miR-4460; R-30b; hsa-miR5p;
RB1 5925 hsa-miR5p; R-4801; R-4432; hsa-miR-7; hsa-miR5p;
.PLK1 5347 hsa-miR5p; hsa-miR-4660; hsa-miR-3665; hsa-miR-3166; hsa-miR5p;
aum l)l unv l
‘AURKA 6790 hsa-miR-3941; R5p; R5p; R3p; hsa-miR-
4757-5p;
BORA 79866 hsa-miR3p; hsa-miR3p; hsa-miR5p; hsa-miR3p; hsa-miR-
3189-5p;
ILK 361 1 hsa-miR-1908; hsa-miR-4505; hsa-miR-744; hsa-miR-4425; hsa-miR-3150a-3p;
K|F1 1 3832
VEGFA 7422 hsa-miR-3668; hsa-miR-939; hsa-miR-29a; hsa-miR5p; hsa-miR-16;
VEGFB 7423 hsa-miR3p; hsa-miR3p; hsa-miR3p; hsa-miR-193a-5p; hsa-miR-
1275;
VEGFC 7424 hsa-miR-711; hsa-miR5p; hsa-miR3p; R-128; hsa-miR-4318;
VEGFD 2277 hsa-miR-320e; hsa-miR-135a; hsa-miR-7; hsa-miR-1184; hsa-miR-513b;
SISEINEIEJOIEJNV FLT1 2321 hsa-miR-148a; R-5095; hsa-miR-335; hsa-miR3p; hsa-miR-149;
KDR 3791 hsa-miR-4435; hsa-miR-665; hsa-miR-370; R-136; hsa-miR-138;
FLT4 2324 hsa-miR3p; hsa-miR-2861; hsa-miR5p; hsa-miR3p; hsa-miR-
4783-5p;
PDGFA 5154 hsa-miR5p; hsa-miR-3917; hsa-miR-4706; hsa-miR5p; hsa-miR-412;
PDGFB 5155 hsa-miR-3202; hsa-miR-1909; hsa-miR-3689d; hsa-miR-4271; hsa-miR-625;
PDGFRA 5156 hsa-miR3p; hsa-miR-4471; hsa-miR-34a; hsa-miR-663b; hsa-miR3p;
PDGFRB 5159 hsa-miR-1915; hsa-miR-4292; hsa-miR5p; hsa-miR-637; hsa-miR3p;
Kit 3815 hsa-miR-4254; hsa-miR5p; hsa-miR-1193; R-222; hsa-miR-4485;
THBS1 7057 hsa-miR5p; hsa-miR3p; hsa-miR5p; hsa-miR-634; hsa-miR-4443;
TGFB1 7040 hsa-miR-3196; hsa-miR-663; hsa-miR5p; hsa-miR-3943; hsa-miR-3183;
SNIlEIIOdOISNV ANGPT1 284 hsa-miR-153; hsa-miR-4643; hsa-miR5p; hsa-miR3p; hsa-miR3p;
ANGPT2 285 hsa-miR-135a; hsa-miR-1182; hsa-miR-513c; hsa-miR-597; hsa-miR-4251;
1 9068 hsa-miR5p; hsa-miR-586; hsa-miR-4480; hsa-miR-544; R-194;
ANGPT4 51378 R5p; hsa-miR3p; hsa-miR-422a; hsa-miR-431; hsa-miR-665;
T|E1 7075 hsa-miR-3151; hsa-miR-4447; hsa-miR5p; R3p; hsa-miR-4287;
TEK 7010 hsa-miR5p; hsa-miR-300; R3p; hsa-miR-150; hsa-miR-148a;
CD274 or 29126 hsa-miR-4443; hsa-miR3p; hsa-miR-138; hsa-miR5p; hsa-miR-1273;
PDL1
Joaempow OanNINI PDCD1LG2 80380 hsa-miR-20a; hsa-miR-548an; hsa-miR5p; hsa-miR-3133; hsa-miR-3910;
PDCD1 5133 hsa-miR-4290; hsa-miR-1291; hsa-miR5p; hsa-miR-2861; hsa-miR-661;
CTLA4 1493 hsa-miR5p; hsa-miR5p; hsa-miR-4254; R5p; hsa-miR-1587;
LAG3 3902 hsa-miR-4515; hsa-miR-1269; hsa-miR3p; hsa-miR-4270; hsa-miR5p;
P|K3CA 5290 hsa-miR-4450; hsa-miR3p; hsa-miR-302d; hsa-miR-3910; hsa-miR5p;
P|K3CB 5291
P|K3CD 5293 hsa-miR-4537; hsa-miR5p; hsa-miR-523; hsa-miR-7; hsa-miR-484;
P|K3CG 5294 hsa-miR-370; hsa-miR-3135b; R-1976; hsa-miR-1276; hsa-miR-3672;
B 5287 hsa-miR3p; R5p; hsa-miR3p; hsa-miR-3612; hsa-miR-4314;
P|3K PRKCB 5579 R5p; hsa-miR-448; hsa-miR-7; hsa-miR-668; hsa-miR-27a;
PRKCA 5578 hsa-miR5p; hsa-miR5p; hsa-miR-4706; hsa-miR-1275; hsa-miR-4525;
P|K3R1 5295 R3p; hsa-miR5p; R3p; hsa-miR-1184; hsa-miR-
4660;
P|K3R2 5296 hsa-miR5p; hsa-miR-3180; hsa-miR-4447; hsa-miR-3960; hsa-miR-3151;
P|K3R3 8503 hsa-miR3p; hsa-miR-4435; hsa-miR5p; hsa-miR-2115; hsa-miR-4313;
HGF 3082 hsa-miR-4520a-3p; hsa-miR-764; hsa-miR3p; hsa-miR-1288; hsa-miR-4710;
MET 4233 R5p; R-2682; hsa-miR-34c—5p; hsa-miR-182; hsa-miR-1269b;
AXL 558 hsa-miR-3142; R5p; hsa-miR-924; hsa-miR-3689c; hsa-miR-432;
MST1 R 4486 hsa-miR5p; R-218; hsa-miR-1286; R5p; hsa-miR-4284;
WO 93212
MAP2K1 5604 hsa-miR-4323; hsa-miR3p; hsa-miR-758; hsa-miR-34a; hsa-miR-15b;
MAP2K2 5605 hsa-miR-1181; hsa-miR3p; hsa-miR-744; hsa-miR-663; hsa-miR5p;
MAP2K3 5606 hsa-miR-4313; hsa-miR-3151; hsa-miR-4283; hsa-miR-4540; hsa-miR-4270;
MAP2K4 6416 hsa-miR-4663; hsa-miR-25; R3p; hsa-miR5p; hsa-miR-627;
MEK MAP3K1 4214 hsa-miR-4286; hsa-miR3p; hsa-miR3p; hsa-miR-544; hsa-miR-887;
MAP3K2 10746 hsa-miR-519d; hsa-miR-651; hsa-miR-587; hsa-miR-34c-3p; hsa-miR-2909;
MAP3K3 4215 hsa-miR-661; hsa-miR3p; hsa-miR-544b; hsa-miR3p; hsa-miR-4505;
MAP3K4 4216 hsa-miR-1204; R5p; hsa-miR-5047; R3p; hsa-miR
MAPK3 5595 hsa-miR-4270; hsa-miR3p; hsa-miR5p; hsa-miR-608; hsa-miR-1291;
MAPK1 5594 hsa-miR5p; hsa-miR-4459; hsa-miR-4271; hsa-miR5p; hsa-miR-2110;
KSR1 8844 hsa-miR3p; hsa-miR-4440; hsa-miR-4291; hsa-miR-4660; hsa-miR3p;
MAPKT 5600 hsa-miR3p; hsa-miR5p; hsa-miR-4292; hsa-miR-4532; hsa-miR5p;
BCL2 596 hsa-miR-448; hsa-miR3p; hsa-miR-3199; hsa-miR-3943; hsa-miR3p;
OdV BCL2L1 598 hsa-miR-4447; hsa-miR-608; hsa-miR5p; hsa-miR3p; hsa-miR5p;
'llNV ERC5 332 hsa-miR3p; hsa-miR3p; hsa-miR-4660; hsa-miR3p; hsa-miR-1273;
MAP 331 R-377; hsa-miR-3150a-3p; hsa-miR-3175; hsa-miR-5095; hsa-miR5p;
BAK1 578 hsa-miR-4419a; hsa-miR-125b; hsa-miR5p; hsa-miR-1909; hsa-miR-4739;
FGF1 2246 hsa-miR-4297; hsa-miR-3155; hsa-miR-1909; hsa-miR-566; R5p;
FGF2 2247 hsa-miR-195; hsa-miR-4524; hsa-miR-503; hsa-miR-646; hsa-miR5p;
FGF3 2248 hsa-miR5p; hsa-miR-4487; R-760; hsa-miR3p; hsa-miR3p;
FGF4 2249 hsa-miR5p; hsa-miR3p; hsa-miR-4290; hsa-miR3p; hsa-miR
;hEa-miR-4435;
FGF5 2250 hsa-miR5p; hsa-miR-4288; hsa-miR-4463; hsa-miR3p;
FGF6 2251 hsa-miR3p; hsa-miR-548q; hsa-miR-138; hsa-miR-639; hsa-miR-1322;
FGF7 2252 hsa-miR5p; R5p; hsa-miR-195; hsa-miR-3920; hsa-miR-1253;
FGF8 2253 hsa-miR3p; hsa-miR-545; hsa-miR5p; hsa-miR3p; hsa-miR
;hEa-miR-1273c;
FGF9 2254 hsa-miR5p; hsa-miR3p; hsa-miR5p; hsa-miR-3683;
FGF10 2255
FGF11 2256 hsa-miR3p; hsa-miR-4469; R-3192; hsa-miR-3661; R-3649;
FGF12 2257 hsa-miR5p; hsa-miR-3202; hsa-miR-4533; hsa-miR3p; hsa-miR-197;
FGF13 2258 hsa-miR-1262; hsa-miR5p; R-1185; hsa-miR3p; hsa-miR-4421;
FGF14 2259 hsa-miR-4663; hsa-miR3p; R-4299; hsa-miR5p; hsa-miR3p;
FGFR1 2260 hsa-miR-4530; hsa-miR5p; hsa-miR3p; hsa-miR-1208; hsa-miR5p;
FGFR2 2263 hsa-miR5p; hsa-miR3p; hsa-miR3p; hsa-miR3p; hsa-miR-
3675-5p;
FGFR3 2261 hsa-miR5p; hsa-miR3p; hsa-miR3p; hsa-miR-3918; hsa-miR-1291;
FGFR4 2264 R3p; hsa-miR5p; hsa-miR3p; hsa-miR-378g; hsa-miR-564;
mTor 2475 hsa-miR3p; R3p; hsa-miR-496; hsa-miR-1233; hsa-miR-1229;
AKT1 207 R-1915; hsa-miR-4721; R3p; hsa-miR5p; hsa-miR
mTOR -AKT-
PTEN-
AKT2 [\3O O) hsa-miR3p; hsa-miR-29b; hsa-miR-4278; hsa-miR-3943; hsa-miR3p;
PTEN 5728 hsa-miR-642b; hsa-miR5p; hsa-miR-148a; hsa-miR5p; hsa-miR5p;
TSC1 7248 hsa-miR-130a; hsa-miR-1537; hsa-miR-637; R-3141; R-3684;
ldMllN Joaempow TSC2 7249 hsa-miR-4420; hsa-miR3p; hsa-miR5p; hsa-miR5p; hsa-miR
STK11 6794 hsa-miR-663; hsa-miR-744; hsa-miR5p; hsa-miR-3960; hsa-miR5p;
P|M1 5292 hsa-miR3p; hsa-miR-761; hsa-miR-3689a-3p; hsa-miR3p; hsa-miR-
4436b-3p;
P|M2 11040 hsa-miR3p; hsa-miR-4532; hsa-miR-3654; hsa-miR5p; R3p;
P|M3 415116 hsa-miR-3195; hsa-miR5p; hsa-miR5p; hsa-miR-4467; hsa-miR-637;
KRAS 3845 hsa-miR-3923; hsa-miR-4323; hsa-miR-4447; hsa-miR-513a-5p; hsa-miR-548ag;
NRAS 4893 hsa-miR5p; hsa-miR-1296; hsa-miR-1324; hsa-miR3p; hsa-miR-4271;
HRAS 3265 hsa-miR3p; hsa-miR5p; hsa-miR-4292; hsa-miR-4532; hsa-miR-663;
RAF1 5894
RAF hsa-miR-1291; hsa-miR-7; hsa-miR5p; hsa-miR5p; hsa-miR-764;
BRAF 673 hsa-miR-617; hsa-miR-2110; hsa-miR-3977; hsa-miR-1182; R-1289;
TERT 7015 hsa-miR5p; hsa-miR5p; hsa-miR-4651; hsa-miR-3687; hsa-miR-4292;
EISVHEIINO'IEIJ. TERC 7012
TEP1 7011 hsa-miR-1911; hsa-miR-3132; hsa-miR-136; hsa-miR-2861; hsa-miR-31;
HSP90AA1 3320 hsa-miR5p; hsa-miR-632; hsa-miR-519e; hsa-miR3p; hsa-miR-134;
DKC1 1736 hsa-miR3p; hsa-miR-621; R-3620; hsa-miR-646; hsa-miR-4279;
PTGES3 10728 hsa-miR5p; hsa-miR-3135; hsa-miR-4266; hsa-miR3p; hsa-miR-4286;
|GF1 3479 hsa-miR3p; hsa-miR-1275; R-4435; hsa-miR-488; hsa-miR-625;
|GF2 3481 hsa-miR-4447; R5p; hsa-miR-210; hsa-miR-3191; hsa-miR5p;
:l9l |GF1R 3480 hsa-miR3p; hsa-miR-4784; hsa-miR3p; hsa-miR-4327; hsa-miR
’9 5p;
BanJeM |GF2R 3482 hsa-miR3p; hsa-miR-653; hsa-miR3p; hsa-miR-4736; hsa-miR-548an;
INSR 3643 hsa-miR5p; hsa-miR-3975; hsa-miR-3188; hsa-miR3p; hsa-miR-4290;
|RS1 3667 hsa-miR-660; hsa-miR-541; hsa-miR-4462; hsa-miR-544b; hsa-miR-183;
PKM2 5315 hsa-miR-762; hsa-miR-625; R-612; hsa-miR-4675; hsa-miR5p;
CDH1 hsa-miR3p; hsa-miR5p; hsa-miR-3689c; hsa-miR5p; hsa-miR-
1296;
CTNNA1 1495 hsa-miR-1288; hsa-miR-4440; hsa-miR-4515; hsa-miR-4705; hsa-miR-9;
CTNNB1 1499 hsa-miR5p; hsa-miR3p; R5p; R-4496; R-
3619-3p;
WNT 1 7471 hsa-miR-4488; hsa-miR-4784; hsa-miR5p; hsa-miR-4644; hsa-miR-4689;
WNT FZD1 8321 R-4269; hsa-miR5p; hsa-miR-1275; hsa-miR-1324; hsa-miR-4279;
WNT5A 7474 hsa-miR-2110; hsa-miR5p; hsa-miR5p; R3p; R-4656;
WNT5B 81029 hsa-miR-4316; hsa-miR-4258; hsa-miR-2909; hsa-miR-1296; hsa-miR3p;
FZD5 7855 hsa-miR5p; hsa-miR-3943; R3p; hsa-miR-3661; hsa-miR-3672;
WI F1 11197 hsa-miR-1972; hsa-miR-3938; hsa-miR-548v; hsa-miR3p; hsa-miR-3977;
DKK1 22943 hsa-miR-493; hsa-miR3p; hsa-miR5p; hsa-miR-4678; hsa-miR-934;
PARP1 142 hsa-miR-891b; hsa-miR-4536; R-4451; R-555; R-7;
BRCA1 672 hsa-miR5p; hsa-miR3p; hsa-miR3p; hsa-miR-760; hsa-miR-4656;
XRCC1
RAD54L 8438 hsa-miR5p; hsa-miR3p; hsa-miR-3918; hsa-miR3p; hsa-miR-
1291 ;
RAD54B 25788 hsa-miR-587; hsa-miR-4268; hsa-miR-548s; hsa-miR-3926; hsa-miR-1;
PARP
ATM J>7 [\J hsa-miR-892b; R-193a-3p; hsa-miR3p; hsa-miR-4736; hsa-miR-4262;
ATR 545 hsa-miR5p; hsa-miR-383; hsa-miR5p; hsa-miR3p; hsa-miR-586;
CHEK1 1 1 1 1 hsa-miR5p; hsa-miR-541; hsa-miR-1286; hsa-miR3p; hsa-miR-16;
CHEK2 11200 hsa-miR-3118; hsa-miR-759; hsa-miR-4276; hsa-miR-3938; R-943;
WEE1 7465 hsa-miR3p; hsa-miR5p; hsa-miR-424; hsa-miR3p; hsa-miR-4278;
HDAC HDAC1 3065 hsa-miR-4284; hsa-miR-4292; hsa-miR-4271; R5p; hsa-miR-584;
HDAC2 3066 hsa-miR5p; hsa-miR-3977; hsa-miR3p; hsa-miR-4662a-5p; hsa-miR-
4720-5p;
HDAC3 8841 hsa-miR3p; hsa-miR-1261; R-326; hsa-miR-1302; hsa-miR-4308;
HDAC4 9759 hsa-miR-4292; hsa-miR-4313; hsa-miR5p; hsa-miR3p; hsa-miR-4316;
HDAC5 10014 hsa-miR3p; hsa-miR5p; hsa-miR-4498; hsa-miR5p; hsa-miR-4505;
JAK1 3716 hsa-miR-4252; hsa-miR-4437; hsa-miR-4520a-3p; hsa-miR-323b-5p; hsa-miR-4674;
JAK2 3717 hsa-miR5p; hsa-miR-4468; R3p; hsa-miR3p; hsa-miR-568;
lVlS'MVP STAT1 6772 hsa-miR-4682; hsa-miR-1252; hsa-miR-3119; hsa-miR3p; hsa-miR-2682;
STAT2 6773 R-665; hsa-miR-3202; hsa-miR-4292; hsa-miR-4313; hsa-miR-1289;
STAT3 6774 hsa-miR-1299; hsa-miR5p; hsa-miR-1184; hsa-miR-874; hsa-miR-5047;
SOCS1 8651 hsa-miR5p; hsa-miR3p; hsa-miR3p; hsa-miR3p; hsa-miR-
324-5p;
SHH 6469 hsa-miR-1471; hsa-miR3p; hsa-miR-4313;
PTCH1 5727 hsa-miR5p; hsa-miR-564; hsa-miR-1262; hsa-miR3p; hsa-miR-125a-3p;
90HE|EJGEIH SMO 6608 hsa-miR-370; hsa-miR3p; hsa-miR3p; hsa-miR3p; hsa-miR-1915;
STK36 27148 hsa-miR-571; hsa-miR-3192; hsa-miR-581; hsa-miR-920; hsa-miR5p;
PRKACA 5566 hsa-miR5p; hsa-miR5p; R-608; hsa-miR5p; R-625;
SUFU 51684 hsa-miR-3184; hsa-miR-4487; hsa-miR-4688; R5p; hsa-miR-4741;
GL|1 2735 R-3943; hsa-miR-4279; hsa-miR-4292; hsa-miR3p; hsa-miR-4533;
ERCC1 2067 hsa-miR-661; hsa-miR-1913; hsa-miR5p; R-1972; hsa-miR-1268;
RAD52 5893 hsa-miR3p; R3p; R3p; hsa-miR3p; hsa-miR-
4303;
VNG XRCC4 7518 hsa-miR5p; hsa-miR-380; hsa-miR-4520a-3p; hsa-miR5p; hsa-miR-
HIVdEIH 2355-3p;
RAD51 5888 hsa-miR-198; hsa-miR3p; hsa-miR-606; hsa-miR-4430; hsa-miR-4432;
BRCA1 672 hsa-miR5p; hsa-miR3p; hsa-miR3p; hsa-miR-760; hsa-miR-4656;
NEDD8 4738 hsa-miR3p; hsa-miR5p; hsa-miR-665; hsa-miR-1285; hsa-miR-1322;
NAE1 8883 R-4524; hsa-miR-646; R-4660; hsa-miR5p; hsa-miR-603;
NOTCH1 4851 hsa-miR-4313; hsa-miR-4268; hsa-miR-449a; hsa-miR5p; R5p;
Adam17 6868 R-507; hsa-miR-3918; hsa-miR5p; hsa-miR-3651; hsa-miR-1827;
PSEN1 5663 hsa-miR3p; hsa-miR3p; hsa-miR5p; hsa-miR-4303; hsa-miR-488;
HOlON NCSTN 23385 hsa-miR5p; hsa-miR-4654; hsa-miR-1321; hsa-miR-4648; hsa-miR-3657;
JAG1 182 hsa-miR-4692; hsa-miR-1273g; hsa-miR-920; hsa-miR5p; hsa-miR-4283;
SRRT 51593 hsa-miR3p; hsa-miR-3190; hsa-miR-487b; hsa-miR-520f; hsa-miR-3929;
APH1A 51107 hsa-miR3p; hsa-miR-198; hsa-miR3p; R5p; hsa-miR-3131;
ROS1 6098 hsa-miR3p; hsa-miR3p; hsa-miR-33a; hsa-miR-606; R-3659;
memo ALK 238 hsa-miR-642a; hsa-miR-646; hsa-miR3p; hsa-miR-1271; hsa-miR3p;
RET 5979 hsa-miR-544; hsa-miR5p; hsa-miR-510; hsa-miR-31; R-3622b-5p;
UBA1 7317 hsa-miR3p; hsa-miR-762; hsa-miR5p; hsa-miR-3202; hsa-miR-31;
Table 12: Mutational status
_ P53
80_SNP_A>G_R-Arg_exon6,
—| —| 102_de|etion_C_exon8
p.G|y12Va| 39_G>A_Met>||e_exon7,
(G12V) WT E_l E_l 75_G>C_exon7
Ii 47_G>T_Ser>||e_exon7,
WT E_| 51_C>A_Ser>Ser_exon7
c.2883T>G
p.||e961 Met
(I961 M)
AGVGD:C|ass
E_l E_l C0_exon 24 —|
c.34G>K
p.G|y12Cys
G12C WT —| —| —| —|
c.35G>R
G12D —|
—| E —| 3_C>T_G| >G| _exon7
p.G|y12Cys
G12C WT —| —| —| —|
c.35G>K
p.G|y12Va|
G12V WT WT E_| E_|
c.3075C>T
WT WT rST 7849079 WT WT 139_A>G_G|u>G| _eX0n5
p.G|y12Va|
G12V WT WT WT W—|
WT T iT T 17_G>T_exon10
c.35G>R
p.G|y12Asp
(G12D) WT WT WT WT WT
WT i—| —| WT _Asp>Tyr_exon5
WT —| WT (0—\6_G>C_Va|>Leu_exon5
62_G>A_G|y>Asp_exon7, and
WT nd 88_insertion_G_exon7
c.34G>K
p.G|y12Cys
(G12C) WT WT WT
c.34G>K
p.G|y12Cys
G12C —| WT 94_G>A_Aro xon5
WT T WT 55_G>C_G| >A|a_exon8
p.G|y12Va|
(G12V) WT WT WT
c.2184+19G>R
WT NonCodant 7107 WT WT 57_A>T_Aro >Stop_exon8
c.2184+19G>R
é Non Codant rs17337107 WT WT WT
58_insertion_G,
€34 i—| WT WT 75_SNP_G>A_Aro >Aro_exon7
WT WT 42_A>G_Lys>G|u_exon5
+19G>R
Non Codant 7107
Codant
c.1799T>W
p.Val600Glu
WT WT WT (V600E) WT
61 58_G>A_G|y>Ser_exon6
65_T>A_Met>Lys_exon7,
70_G>A?_Gly?>Arg?_exon7,
129_C>T_exon7
-c2184+19G>A_Non Codant rs17337107
47_G>T_Ser>||e_exon7
51_C>A_Ser>Ser_exon7,
WT wt wt wt 83_C>A?_Pro?>His?_exon7
p.Val774delinsAIaLeu exon 20
c.35G>S
p. G|y12A|a
G12A WT 152_insertion_T_exon5
Non Codant rs17337107 WT WT WT WT
83_T>C_exon7
55_A>G_Tyr>Cys_exon6
p.G|y12Cys
G12C WT WT WT WT WT
163__A>THis>Leu_exon5
p. G|y12Cys
(G12C) WT WT WT WT WT
96_G>T_VaI>Phe_exon5
158_C>G_ex0n7
91 80_SNP_A>G_R-Arg_exon6,
. 101_A>G_G|u>G|y_exon7,
p. G|y12Cys c.2184+19G>R 106_T>A_Ser>Thr_exon7
Non Codant rs17337107 142_C_>Gexon7
----—pLS739Ala743deexon20
c.2156G>C p. G|y719A|a
) VAR_026086 exon 18
c.2303G>T p. Ser768lle (S768I)
WT AGVGD:Class C65 exon 20 WT WT WT WT
94 c.34G>K
p. G|y12CysW
G12C
c.34G>K
p. G|y12Cys c. 2184+19G>R
(G12C) Non Codant rs17337107 WT WT WT W_T>C_Tyr>HiS_exon6
103 c.2184+19G>R
Non Codant rs17337107
c.35G>K
p. G|y12Va|
G12V WT WT WT WT WT
70_C>T_Arg>Trp_exon7
71_SNP_G>A_exon7
108 WT 26de|etion_T_exon9
111 c.2313_2314in59bp (CCCCAGGCG)
p.Pr0772_Hi5773insGlnAIaPro_eXpn
WT 20 WT WT WT WT
p.G|y12Cys
(G12C) WT WT WT WT WT
115 c.2184+19G>R
WT Non Codant rs17337107 WT WT WT WT
WT 99 ->G| _exon5
c.183A>W
p.Gln61 His
(Q61 H) 92_C>T_exon5,
rs17851045 104_C<T_exon5,
exon 3 WT WT WT WT 128_C>G_Ser>Arg_exon8,
Table 13: Calculated scores
Wherein P means t, (1) refers to a score calculated based on mRNA expression, (2)
refers to a score calculated based on mutation and mRNA expression, (3) refers to a score
calculated based on mutation, mRNA expression, and miRNA expression, and (4) refers to a
score ated based on mutation, mRNA expression, miRNA expression and Copy Number
Variation.
8 4
P PLK_ URKA_Kinesins ANGIOGENESIS ANGIOPOIETINS
1 2 2
2 --—_-—-ElEl5 5
3mm1
4 Ifl-I—__-lfl8 8
EIE__-—Elflfl8 8
8 Hnn8 8
7 5 5
8 mum—”n2 2
8mm1
8 8
11 0 10
12 --—_-—-ElEl5 5
18 III—mu1 1
14 Elfl__—Ellln10 10
1 4
18 ElEl__—El-Elll10 10
17 --—_-—flElEl8 8
18 ---__l_-El7 7
18 --—_-E-=IEI8 8
[HI—mun7 7
21 l__-—--l"fl8 8
22nun—m5 5
281010
24mm1
2
m 1 1
2 uua mm
28 ---—2 2 1 003mV 5 003mV
31 III— 1 1
32 ---—5 5
%M% manmannun 8m669433m8 7m589646m5 89646m5
36 anan 1 1 0 1 0 1 0
w33 uun
9 10--—62175mm59363_/4wnlV 5003
m 4 4 4 4 2
41 ---—5 5 3 3 .5
42 8m669433m8047525m45719687442153937148396211 m414m73347135 m414m73347135
%M% manmanman 576 W567 1 1
446 5 5 3 2 2 7 10--—47100 47100
w uuu
49 II- 5 5
50 III51 1
51 III3
&%M%% mannagunmanmanna m6mm3739
57 ---1O4
58 10 In 9
59 “10
m 1324700221
an n 0d
0221
61 an 3
62 Im—
w nnn 8 87776711449672263
64 III—2 2 1 1 _/
%%m manmanman 317m49m6mm8711 4 35512 35512
1 114 2 2
oO15oOOu_/;.n|u3;.nlV 5;.n|V4_5_/10u6oo_/4421539.371400396211100150097wnluoownlV .5832.5m5672oo7776711449672263742114oo1_/000u5;.n|u2;.n|V 817
u2wnlV 42mm782 42mm782 74m6mw514m733461367582885m9142488221884641272633mm7927 W84663521m9247889884255492123757422m52m35938m7m11m761 m8m663521m9247889884255492m23757422m5mm35938m7m11m761 m9m763632m8246879894346382m23767433m5m925839m8m11m851 mnmn“nunnmnnnnumnnnnmnnnnnmnnnunnnmmnmnnmnmnmnmnmmnmn mnnn“mannmnnnnannmnnmnannnnnnnunnnmnnnnmnnnnnnnmnnnnn mnnn“mannmnnnnannmnnmnannnnnnnunnnmnnnnmnnnnnnnmnnnnn 1093780516927184940435367934569005476827826628389044463 10937000.516003710049404352679345600005476927826628399034463
80 --_ 71
2 2 417 41;.nlV 1
82 --_11 3 3 10 10
7 1 1 1
84 III5 5 5 4 4
85 III4 4 5 2
8888 6789 sunm4sunm4-4nnm 4003 4003
90 a 0
91 ---—2
92 I“— 93“—71421 71421
9945 ananan 1 1
96 ---—7
99 789m man“nun“nnnn
01 “Ell! 253472 253472
%M%%W% 1 4mmna 8W5 8W5
1 1
0 75300 75300
1111111111 4;.nlu44;.nlu_/oo;.n|V 4;.nlu44;.nlu_/oo;.n|V 1 1
22 9012345678901 .n-nnnnannmnaannnnn 4mnnnnnnamnmnmamnnnn 79734mmm61m125694mm253284m392m156228 439272m27719262397m5958762368646m59275 439272m27719262397m5958762368646m59275 429465m2881924318996m6854335763493m387 00001924318896m68543357634m3m377 1730512289554592033282179174.0819914307476206
5 982377582m691431m14236299m66543753m44m68955 936400461526W46379677537m4W8974963279139 936400461526W46379677537m4W8974963279139 1mwmwOo454005726279452795764_.G_/;.n|u2wnluoo953;.nlu741r0914;.nlV nnmmumannananannaaannannnnnmnmnnmnmnnnnnnnm nnmammannnmanmmmnnannunnnmnmnmnnnmnmnmnnnmn annnmanmmmnnannunnnmnmnmnnnmnmnmnnnmn mm522299554592033283179174.08198143074763061
nmnnnmmnnmmnnmmnnmmn
IMMUNO-Modulator P|3K
8 8 8
1 46954
1 7004762 7004652
1 m7
2
21 W823 3
22 ”--5 1
7
1 1
26 _m-4
5
10
7 7
5 5 9565453858mmm98972214m797
4 4 m
m 669 ananmmnunnmmmnnnnnmnnmnnnmnmn
37 mmn
3 3
1 1 3W1 man 1m222866121m465988567739181781 .364223200629939142mw6oo3m6oo470051wnlull_/27_/269_.G;.n|u6oo;.n|u647557;.nlV 3645272W528oo3oo132W672m874694191726616m5m98m536449mm79 9565453858mmm98972214m797m6697184681m159561000057006.6949 6001
2 4 4 a 3 8
3 3 n 756mV 700
99 7m 4
9 nunnmmnnnnmnnnnnmnnmn anaammaunnmmmnnnannnnmnnnmnnnununmnnmnnnnnmmnnnnnnnmn umnnanamnnnnnnnaannnnannnmnmmmnunnmnmmnnnnnmmnnnmnmnn 0039759551000092725544002576231m352628m25m861693m74118369 740043.loo329mwgz527656mm300673440027.3537m2_.G;.HIV96;|496;.nlu64110026;.nlV 640073700329ng2427656mm39673440027.3537m2_.G;.HIV96;|49_.G;.nlu64110026;.nlV 2614530014400934oo4W652mm4636157648288673176739531 4422522614530014400934oo4W652mm4636157648288673176739531 EnflmmnmmnHEnEmumum"MEEmumum“Innmnnmmflflnflmnflmflmmmnflmmfl
61 1 1 5 1 5 3 3 10 8 10 1o 10 u-
62 3 3 2 2 8 8 8 8 8
63 8 8 ——nnn9 9 9 1 1
64 1 1_-5 3 5 5 5 3 3 3 8 8 an
65 7 7 1 1 1 9 9 m
88 mm-10 7 7 3 3-_--
67 5 5 _-—---—--4 4 1 1 1
68 8 8 ——nnn9 8 8 8 8
89m- 0
70 112 1 1 1 1 3 2 2 1 1
71 _7 7 n—n-n7 7 7 10 10
72 2 2_-3 8 5 3 3 3 5 2 [6|-
73 8 8 1o 10 -_--8E 9 9 --
74 1o 10 _—--I§I8 9 598132221 298189141147511778 8 --
75 3 3 __flfl-3 1100 I“
76 1 1 _--2 3 8 an
77 mm_---4 2 9 II-
78_--2 0 10 n7n
79 1 4 8 3 2
80 __--fl-3 2 1 0 --10 1 0
___fl--5 4 3 3 I5 3 3 3 --
83 __-_1---8 7 5 5 an
84 ___fl--2 10 10 1O In
85 __E5—£21g2 8 8 8 II“
88 mm-2 3 2 3 2 2 00 1“-I]-
87”mm4 5 5 an
88 4 4 4 4-10 10 10 7 7 In“ 6 6 6 In
89 3 3 1 3 2 4 4 III-fl—6 8 8 14m14750m778
90 7 7 7 8E8 9 1 0 3 -2
912_n——--nnn6 92
92 5—n—“_-n-
93 7—-—--n9 9 9 [6]-
941__---1 1
95 1__---10 10 110
98 3_-—---4 1 110 32853 an--I-
97 m_-m---1 1 1 5--
98 mm“8 5 “EE8 8 8 3--
99 3__--n9 7 7 I-
11111111111111002__--- 5 4 4 1 an
012__---10 10 9 --
10 10 an
032__---7 7 7 In
04m10 10 I] 9 9 9 8 8 an- 1 4 4 an
05 --75 9 9 n-
083__flfl-44 4 --
072__---7 5 5 an
08 __-_8---10 7 7 an
09murm-5 5 5 an
__-_3---7 8 8 8--3:0288297599
111__---5 4 4 2mm
12 __-_1---1 1 1 10““
13 __-_---4 3 3 9232853539028829759962011 1--
-5 annannnnannnnnnnn
I!I!nmnnnnnnn
I]I]
-3 “Immunnnnnnu
1 2 4 1 3 1 2 3 2 mn_4
D. mTOR AKT Modulators mF Telomerase
AntlapoptOSIs PTEN MTKPT RAS
1234567009 10 mmm42m2 10 6
mm4292 10 34210 0
.554
1111111111 012345670090 1 1
0 0
1002;.nlV nlV 13441
1 1
2 8 0 0
2345 2
458m45 7m182457m45 5111.527
150 0
28 0 444678724841635519392364675589 77
333345 9m41mm mm41mm 140 0
W218m3 W218m3 0 373m974486 444678724841635519392364675589m373m974486 522730041232775772m4531m98m649m83559m95186 685m24475mm8m511212563325892934697396m855 673m284659m7m6112223433369m2m25690020079745 748868245121647m257m1849m73479m2297341663 88682m512m647m257m18m9m734m9mm297341mm3 73m284659m7m6112223433369m2m25690020079745 342m985737m44315311m7369m5886684937979855 .510 0
.5 150059929421372744708551099299891102874462
43 an 7635
1
5743 1
455 nan 21770063930000.3400 11421778639388.3400 4004_/364401674240016001;.nlvwnlV 412752328mm8875m7m6m13
953
1 1mm" 39
1 0 m 392mm
1 0 “4 004006165574731m9m9139m584m3595m6312121
34 mnmmnnm
7 nus "flmm 9m1161954287m1m61 953m397392mm29m1161954287m1m61 5258m984938m19m9232758387m3931 99963128281141166m667711349833 311661429mm7876m6m891530000966149591131165945582155m743 500632m76653111931117W8383562765m88m5m9743m46929524279 5863mm76653111931117W838356276mm88m5m9743m4692952m27m 311661429mm7876m6m891530000966149591131165945582155m743 65889693269m2 30047208883371206614005561500373205m35390226466137054611111111
1 0 nn 9265m28m7m4m185521867265295 9265m28m7m4m185521867265295 9215626m6147124731655669367 25 2 4W3 234 0
34
aInna 7 2 7
0 1
05 35113 35
00 1 0 0 1
8 8
5517100 55m7m
m 0 669442377979483m84479m75 4843277985m482m84359m77 4332mm52m956m891938554671498 m52m9m6m891938m5467149m 985m482m84359m77 2m77344725616m74122481m2278 937188409176062563765784934
----1 3 4 2 3 1 3 4 2 m3 4 1 2
F WNT PARP HDAC JAK_STAT HEDGEHOG
6 4 4
WO 93212
24 unn_--n9 9
10 8 1o 9 1o 10 1 1 n
28 n-_nnn7 7 I]
27 1---—---n—9 9
28 10 2 2 I!
29 3 8 5 5 4 110 10
10 “II 8 1o 9 9 10 2 2 I!
31 -”I7 9 1o 10 10“10 10
32 “MEI—I“—3 2
33 1--I_---—-8 8
34 4 I!” 9 9 10 1o 10 Ill]- 2 4 n
10 "I! 4 4 1o 10 8 flfl_-4
38 10 --—---n3 3 I]
37 3 10 4 9 9 8 flfl_-
38 10 ---—---—ll3 3
39 nun-I—nnn—8 7
40 1---—----—2 2
41 m-8 4 1 1 5 “fl- 4 4 I!
42 “In“ 5 3 3 3 410 10 [6]
43 “nun—"n
44 4 8 4 1 1 2---—-
45 1 I!
48 2 ---—----—69928286529591933953481 86529591933953481
47 5 10 1o 8 8 8 an- 10 10n
48 2m—”—- 1
49 3 “El 9 7 1o 10 7 “I‘ll! 8n
50mm 8n
51 5 III—null
52 fl"_---—-
53 10 3 8 8 8 8 nn_-
54 5 --—---I=I 8 fl
55 “I4 4 3 3 8 flfl_-
58 unn- 5 9 7 8 9 an- 17831674956241 8
57 “III—“fl10 11783167585624109868203994941 0067176700432 7nI!4 58 4m—”—-9
59 “nun—“In—8
60 1 10 1 2 2 6 --_-1 2
81man“5 1
82 5 --—---El2 1o 10 n
83 10 10 1 7 7 fl
84 nunI_---3 1010-
65 Elm—III]9 9 9 n
88 1 m—”—-9 4
87 2 2 2 1 1 1
88 -“l=l 1 8 5 5 2 ---l_
69 2 4 3
70 3 1
71 “_l=ll=l10 10 8 8
72 “In—II-3 3 3 3
73 “III—II-4 4 1o 10-
74 2 --l=_---—llo o
75 10“—u—Ifln4 3
78 2 1 9 9 9 8 nn_-
77 5 1 6 4 4 1 “I! 6
78 5 fl” 7 8 6 6 1 2
79 10 10
80 1 ---—--I§I 9 I]
82 “II—“fl 6 [6|
83 “nun—“In—3
84 flflfl- 3 3 3 3 9
85 -fl_---EI—-7
86 “HI9 4 7 7 8 “In 9
87 ---—---fl 5 [6]
88 2 2 8 8 8 10nn_-62m946357951
89 flflfl- 5 7 10 10 7 l
9O 1---—-flflfl—1
91 -“l=l 5 2 3 3 4 nn_-
92 In“10 3 6 6 7M1 1 6 1361 [6|
93 2“W
94 7 ---4 1 1 1 8 flfl_-
95 3 ---7 9 7 7 10nn_-
96 4 --—---—2
97 -El-—--—nfl-127
98 2 ---—-_
99 7 ---1 4 4 4 8 7 [6|
1111111111111111111111 00 flflfl- 9 8 9 8 “El- 10 1
01 7
02 5 ---1 10 9 10 007151672275997408134861231 [6]
03 32 --El4 7 8 8 10 10
04-fl_---1 10 47.01767 I!
05fl--_7 77 7 8 4 III3 3 5 6 7 -7
06 ----—flflfl—fl7 7 9 6 5
07fl-II—n—I-4 4 5 4 97 1 1 W
---—-4 4 5 5 6
0 53 5
1111111111 90123456789 nunnnnnnnmnzIII—I-fl—I599 57 57 57
nnnnnnnnnnz unnnnnnnngfl—---—-7 8 5 5 2m
an1 9 8 9 3
1 0 6 7 69 "a 3 1 810 an1
8 7 5 4
8 5 6 4
3 5 7 9
fl—EEI—I71 0 1 0 1723998567988963 4 4 1 0
n—---—-99 8 4 5 5 7 8 4 4
7 6 8 38 5 5 7
--—“n1 1 0 I!
m---_--n—-2 2 2 3 2 5 110071516722759974081348612318066155633459487009 9 176775062m80375m48834 883 3
21 unn_nnn—-9 9 9 4 5
-------------1 2 4
DNA REPAIR NOTCH OTHERS PDL1 CTLA4
nunmmnnnnnn“n
6 0 1
1 1 0123456789 nunnnmnnnmnmnmngnnnn nunnnmnnnmnmnmn 815314181974845447 m26726274814151332 m26726274814151332 0300750020061
1 10
1 10
21 --—3
mBM%
m7 8m693m31 8m693m31 0
m um 1
w m65oo1 0
33 4 4 3 5
%%w%w 0
%M%%M%mwm mnnnnnnngnnnnnnnmngnnnnn mnnnnnmunnmnnnsunnmnnnnngnnnnn W8523824296769 mwmw/I4772594384;.nlV mwmw/I4772594384;.nlV 0
52 --—
wM%%w 0069672357 9100433394 9100433394
58 --—2 2 2 2 2 96914m4521599m92168m791686862m34m3379835731847m156693 96914m4521599m92168m791686862m34m3379835731847m156693 9400654175636m9347m22892m685682184735927m69mm1m6626198 9400654175636m9347m22892m685682184735927m69mm1m6626198 75m6m8433476m3215761997958553m545673m34m5188943614182 82871mm97446975mm7m37555417295382667369m74632198 874469759070375554172953002667368074632197
111 11
w aa m
w 4700 60071 7
% amaama 27-7 8W2 456
5 5 0d
wm mmmaaammaa 31 ma
95 10
%m%9 mamamama 1134
000 123 maa 29 45695694729m52 5694729m52
maammmmm- 00 789085m3 7 1146126145659194001349136841487598467122382235009312751
o9 mamm- 5
m6 m3 aaaaammmaaaammama mmaamaaamammammaaaaaamaaammaaam aaaammaamamaaammaaaaaammaamaaamammaamaaaaaamaaammaaam 9824mm13132865m152357232293m58m64m6244574597897118867 9824mm13132865m152357232293m58m64m6244574597897118867 6327737W3882733m43m91555m112654744712459.351129361009001 6327737W3882733m43m91555m112654744712459.351129361009001 223344369m92438m52721126673466949581128752886m5817677 aaaammaaaaaamaaaaamammaaamamaaamaammmaamaaaaaaaammamm maammmamaaaaaamaamammmamamaaammammamaamamaamaaamaaaaa maammmamaaaaaamaamammmamamaaammammamaamamaamaaamaaaaa 61271456591040013491368414875984681223822365m9312751
4633m46m73 82937 00175482937 173562754wn|V 173562754wn|V 8444295m85 8444295m85 248119mm790 m57m73 m7
Claims (15)
1. A method for determining in a patient having a cancer a classification of intervention points according to the intervention points activation status, wherein 5 - the intervention points comprise the group consisting of the HER, CDK4,6, PLK/AURK/Kinesins, Angiogenesis, Angiopoietins, Immune Modulators, PI3K, MET, MEK, ERK, Anti-Apoptosis, FGF, mTOR, Ras/Raf, rase, IGF/glycolysis, Wnt, PARP, HDAC, JAK-STAT, Hedgehog, NOTCH pathway, DNA Repair, RET, ALK, ROS1 and UB1, or subgroup thereof of at least 10 10 intervention ; and the genes of each intervention point are d according to Table 1 or 9; - the method comprises - characterizing a tumor sample in ison to a normal histologically matched sample from the same patient, including 15 - for each y of the group or up of intervention points, determining the mRNA expression level of the genes of the intervention point as disclosed in Table 1 or 9, y determining a fold change of mRNA expression of tumor vs normal, (referred as mRNA TvN fold change); 20 - wholly or partially cing genes of Table 1 or 9, thereby identifying the presence of activating mutation in the tumor sample; - for each intervention point of the group or subgroup of intervention points, determining the level of miRNAs of the 25 genes of the intervention point as disclosed in Table 11, thereby determining a fold change of miRNAs level of tumor vs normal, (referred as miRNA TvN fold change); - -calculating a mean miRNAs fold change for each gene as the average of the miRNA TvN fold changes for the gene; 30 - calculating a corrected mRNA TvN fold change by dividing the mRNA fold change Tumor versus Normal of the gene (mRNA TvN fold change) by the mean fold change for the miRNAs of the gene (mean miRNA TvN fold change), the ted mRNA TvN fold change of the gene being used to calculate the arithmetic mean of the mRNA TvN fold changes of the genes for each intervention point; - calculating a score for each pathway based on the characterization 5 data, wherein - if, in the tumor sample, the ce of an ting mutation of a gene of an intervention point is detected, then a maximal score is given to the ention point; - a score is calculated based on the arithmetic mean of the 10 mRNA TvN fold changes of the genes for each intervention point of the group or subgroup of intervention points, provided that the mRNA TvN fold change of a gene is taken into consideration only if its value is at least 1.3; and - the score of each intervention point of the group or subgroup 15 of intervention points is either a. the sum of the score due to the presence of an activating mutation and the score calculated by the average of the mRNA TvN fold changes; or b. the score due to the presence of an activating mutation 20 if there is a mutation or the score calculated based on the arithmetic mean of the mRNA TvN fold changes in absence of mutation; and - classifying the intervention points according to the calculated scores. 25
2. The method according to claim 1, n the genes of Table 10 are sequenced for detecting the presence of mutations as defined in Table 10 and p53 gene is sequenced.
3. The method according to claim 1 or 2, wherein, for each ention point of the 30 group or subgroup of intervention points, the method comprises determining the miRNAs level of the genes of the pathway as disclosed in Table 11.
4. The method according to any one of claims 1-3, n the score is from 1 to 10 and the l score given to the ention point is 10.
5. The method according to claim 3 or 4, wherein the level of miRNAs is determined and 5 used to calculate a corrected mRNA TvN fold change for the genes of the following intervention points: mTOR-AKT-PTEN, RAS, ERK, PI3K and Immune Modulators.
6. The method according to any one of claims 1-5, wherein for each intervention point of the group or subgroup of intervention points, the method comprises determining 10 the copy number variation of the genes of the pathway as disclosed in Table 1 or 9, thereby determining a tumor vs normal fold change for the amplified genes.
7. The method according to any one of claims 1-6, wherein the subgroup of intervention points consists in the following group: Her, CDK4,6, PLK/AURK/Kinesins, 15 Angiogenesis, Immune Modulators, PI3K, MET, MEK, ERK, Anti-Apoptosis, FGF, mTOR, Ras/Raf, IGF/glycolysis, Wnt, PARP, and DNA Repair.
8. The method according to any one of claims 1-7, wherein it further comprise selecting a group of three activated or disturbed intervention points in a patient having a 20 cancer, n three intervention points are selected among the intervention points having the highest scores.
9. The method according to claim 8, wherein the three intervention points are the three intervention points having the highest scores.
10. A method for selecting a combination of three drugs useful for treating a patient having a cancer, wherein a group of three activated or disturbed ention points are selected by the method of claim 8 or 9 and a drug is selected for each or disturbed intervention point, thereby providing a combination of three drugs.
11. Use of a kit for classifying pathways according to the intervention points tion status according to the method of claim 1, wherein the kit comprises means for measuring the mRNA expression level of the genes of Table 1 or 9 for intervention points sing the group ting of the HER, CDK4,6, PLK/AURK/Kinesins, Angiogenesis, Angiopoietins, Immune Modulators, PI3K, MET, MEK, ERK, Anti- sis, FGF, mTOR, Ras/Raf, rase, IGF/glycolysis, Wnt, PARP, HDAC, JAKSTAT , Hedgehog, NOTCH pathway, DNA Repair, RET, ALK, ROS1 and UB1, or subgroup 5 thereof of at least 10 intervention points.
12. The use of claim 11, wherein the kit further ses means for detecting the mutations of Table 10. 10
13. The use of claim 11 or 12, wherein the kit further comprises means for measuring the miRNA level of miRNA of Table 11 for intervention points comprising the group ting of the HER, CDK4,6, PLK/AURK/Kinesins, Angiogenesis, Angiopoietins, Immune Modulators, PI3K, MET, MEK, ERK, Anti-Apoptosis, FGF, mTOR, Ras/Raf, Telomerase, IGF/glycolysis, Wnt, PARP, HDAC, JAK-STAT, Hedgehog, NOTCH, DNA 15 Repair, RET, ALK, ROS1 and UB1, or subgroup f of at least 10 intervention points.
14. The use of any one of claims 11-13, wherein the kit further comprises means for determining the copy number variation of the genes of Table 1 or 9 for pathways 20 comprising the group consisting of the HER, CDK4,6, RK/Kinesins, Angiogenesis, Angiopoietins, Immune Modulators, PI3K, MET, MEK, ERK, Anti- Apoptosis, FGF, mTOR, Ras/Raf, Telomerase, IGF/glycolysis, Wnt, PARP, HDAC, JAKSTAT , Hedgehog, NOTCH, DNA Repair, RET, ALK, ROS1 and UB1, or up thereof of at least 10 intervention points.
15. The method of claim 1, substantially as herein described with reference to any one of the Examples and/or
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14305918 | 2014-06-16 | ||
EP14305918.6 | 2014-06-16 | ||
PCT/EP2015/063263 WO2015193212A1 (en) | 2014-06-16 | 2015-06-15 | Method for selecting personalized tri-therapy for cancer treatment |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ725780A NZ725780A (en) | 2021-02-26 |
NZ725780B2 true NZ725780B2 (en) | 2021-05-27 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11124836B2 (en) | Method for selecting personalized tri-therapy for cancer treatment | |
Slattery et al. | The PI3K/AKT signaling pathway: associations of miRNAs with dysregulated gene expression in colorectal cancer | |
Slattery et al. | An evaluation and replication of mi RNA s with disease stage and colorectal cancer‐specific mortality | |
Gaedcke et al. | Mutated KRAS results in overexpression of DUSP4, a MAP‐kinase phosphatase, and SMYD3, a histone methyltransferase, in rectal carcinomas | |
Danielsen et al. | Portrait of the PI3K/AKT pathway in colorectal cancer | |
Gámez-Pozo et al. | MicroRNA expression profiling of peripheral blood samples predicts resistance to first-line sunitinib in advanced renal cell carcinoma patients | |
Aushev et al. | Comparisons of microRNA patterns in plasma before and after tumor removal reveal new biomarkers of lung squamous cell carcinoma | |
Catanzaro et al. | The miR‐139‐5p regulates proliferation of supratentorial paediatric low‐grade gliomas by targeting the PI3K/AKT/mTORC1 signalling | |
Engler et al. | Genome wide DNA copy number analysis of serous type ovarian carcinomas identifies genetic markers predictive of clinical outcome | |
US20150254400A1 (en) | Grouping for classifying gastric cancer | |
Cava et al. | How interacting pathways are regulated by miRNAs in breast cancer subtypes | |
Yang et al. | Modulation of mTOR and epigenetic pathways as therapeutics in gallbladder cancer | |
Mazza et al. | MicroRNA co-expression networks exhibit increased complexity in pancreatic ductal compared to Vater's papilla adenocarcinoma | |
Nagai et al. | High RAD54B expression: an independent predictor of postoperative distant recurrence in colorectal cancer patients | |
NZ725780B2 (en) | Method for selecting personalized tri-therapy for cancer treatment | |
WO2021028768A1 (en) | METHOD FOR ALTERING THERAPY OF ADVANCED NON-SMALL CELL LUNG CANCER PATIENTS BASED ON ANALYSIS OF ctDNA | |
Sánchez-Céspedes | Lung cancer biology: a genetic and genomic perspective | |
Constantin et al. | Molecular pathways and targeted therapies in head and neck cancers pathogenesis | |
EP3665307B1 (en) | Materials and methods for stratifying and treating cancers | |
Pathak et al. | Head Neck Squamous Cell Cancer Genomics: Oncogenes, Tumor Suppressor Genes and Clinical Implications | |
Simeone et al. | Pan-cancer onco-signatures reveal a novel mitochondrial subtype of luminal breast cancer with specific regulators | |
Chan | Multi-Omic Characterisation of Human Angiosarcoma | |
Larriba Tornel et al. | Identification of new targets for glioblastoma therapy based on a DNA expression microarray | |
Narrandes | The qRT-PCR assay and the genomic/epigenomic properties of the 10-gene Yin Yang expression ratio signature in non-small cell lung cancer | |
Fodor et al. | Prognostic epigenetics |