WO2016123054A2

WO2016123054A2 - Kinase drug combinations and methods of use thereof

Info

Publication number: WO2016123054A2
Application number: PCT/US2016/014831
Authority: WO
Inventors: Gary L. Johnson; Lee M. GRAVES; Jian Jin
Original assignee: The University Of North Carolina At Chapel Hill
Priority date: 2015-01-26
Filing date: 2016-01-26
Publication date: 2016-08-04
Also published as: WO2016123054A3

Abstract

The present disclosure relates to method for inhibiting cancer cell growth or inducing apoptosis in cancer cells by inhibiting kinome reprogramming in a combination therapy involving kinase inhibitors. A kinase inhibitor in combination with a P-TEFb inhibitor and/or p300/CBP inhibitor provides a stable growth suppression of the cancer cells, blocking kinome reprogramming response to kinase inhibitors.

Description

KINASE DRUG COMBINATIONS AND METHODS OF USE THEREOF

CROSS-REFERENCE TO RELATED APPLICATION

[1] This application claims priority to U.S. Provisional Application No. 62/107,788 filed January 26, 2015, U.S. Provisional Application No. 62/144,457 filed April 8, 2015, and to U.S. Provisional Application No. 62/195,435 filed on July 22, 2015, and the disclosure of each of which is herein incorporated by reference in its entirety for all purposes.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[2] This invention was made with government support under Grant Nos. GM101141, CA580223, and MH 104999 awarded by the National Institutes of Health. The United States Government has certain rights in the invention.

FIELD

[3] The present disclosure relates to methods for inhibiting cell growth by inhibiting kinome reprogramming with combination therapies including kinase inhibitors, CBP/p300 inhibitors and/or bromodomain inhibitors.

BACKGROUND

[4] Protein kinases play a significant role in the regulation of many cellular pathways. As such, many diseases, including cancer, which are associated with abnormal cellular responses, are triggered by protein kinase-mediated events. However, inhibition of abnormal kinase activity with kinase inhibitors is challenging. Many tumor cells respond to targeted kinase inhibitors with rapid adaptive changes in signaling networks, effectively bypassing the targeted oncoprotein inhibition. This adaptive response to treatment with targeted kinase inhibitors contributes to the failure of single agent kinase inhibitors as an effective therapeutic agent. Virtually all cancer cells treated with a single kinase inhibitor agent develop this adaptive response and become rapidly resistant to the kinase inhibitor.

[5] These rapid adaptive changes in kinase signaling networks (the kinome), as a response to administration of kinase inhibitors, are referred to as kinome reprogramming. Kinome reprogramming is believed to be one of the major reasons for the lack of durable responses in the treatment of cancer patients with kinase inhibitors.

SUMMARY OF THE DISCLOSURE

[6] In one embodiment, the present disclosure provides a method for inhibiting growth of a cancer cell which comprises administering to the cancer cell one or more of a kinase inhibitor in combination with one or more of a positive transcription elongation factor b (P-TEFb) inhibitor, a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor (inhibits CBP and/or p300), wherein the one or more P-TEFb inhibitor, a CBP inhibitor, a p300 inhibitor, and/or a

CBP/p300 inhibitor, is administered in an effective amount to prevent kinome reprogramming and the development of resistance of the cancer cell to the kinase inhibitor. CBP and p300 are two homologous proteins which are lysine acetyltransferases. In some embodiments, the administration of a kinase inhibitor and a P-TEFb inhibitor to the cancer cells can comprise contacting the cancer cell with a kinase inhibitor and a P-TEFb inhibitor. In another embodiment, the administration of a kinase inhibitor and a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor, to the cancer cells can comprise contacting the cancer cell with a kinase inhibitor and a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor.

[7] As used herein, a P-TEFb inhibitor may be an inhibitor that modulates or interferes with the pause/elongation function of RNA polymerase II of P-TEFb that is CDK9/cyclinT and its complex with BRD4, JMJD6 and NSD3. In some embodiments, the P-TEFb inhibitor is a

BRD4 (BET family bromodomain-containing protein 4) inhibitor. In some embodiments, the

BRD4 inhibitors can include, but are not limited to, apabetalone (RVX-208) (see, e.g. , J Am Coll Cardiol 2010 5(23) 2580-2589 and www.chemspider.com/Chemical- Structure.25069708.html), BI2536 (see, e.g. , Steegmaier, Martin et al. Current Biology, Vol. 17 (4), 316-322), bromosporine (see, e.g. , www.thesgc.org/chemical-probes/bromosporine, 12/3/2014), CPI-203 (see, e.g. , Ballachanda N. Devaiah et al., PNAS 2012 109 (18) 6927-6932 (April 16, 2012), I-BET151 (see, e.g. , Dawson, MA et al. Nature (2011), 478(7370), 529-33) , I-BET762, JQ1 (see, e.g. , Matzuk, Martin M., et al. "Small-molecule inhibition of BRDT for male contraception" Cell 150.4 (2012): 673-684; see also Filippakopoulos, P. et al. Nature (2010), 468 (7327): 1067-1073), MS436 (see, e.g. , Zhang et al., J Med Chem. (2013); 56 (22), 9251-64), OTX015 (see, e.g. , J. Kay Noel et al., Mol Cancer Therapeutics (2013), 12, C244), PF-431396 (see, e.g. , Ciceri et al., Nature Chemical Biology 10, 305-312 (2014), PFI-1 (see, e.g. , Picaud et al., Cancer Res. (2013); 73(11): 3336-46), TG-101209 (see, e.g. , Ember et al., ACS Chem Biol. (2014); 9(5): 1160-71), and TG-101348 (see, e.g. , Ciceri, supra), or combinations thereof.

[8] As used herein, a CBP inhibitor, a p300 inhibitor, and a CBP/p300 inhibitor, may be an inhibitor that modulates the acetylation of histones, such that BET bromodomain activity (e.g., BRD4), by reducing or modulating in a way that interferes with the pause/elongation function of RNA polymerase II of P-TEFb downstream. BET bromodomain proteins bound to acetylated histones recruit proteins regulating RNA polymerase II and transcription. In some embodiments, the CBP inhibitor, the p300 inhibitor, and/or the CBP/p300 inhibitor, can include, but are not limited to, SGC-CBP30 (see, e.g. , J. Am. Chem. Soc. 2014 1369308-9319), BDOIA383 (see, e.g. , Brennan, P. (2012). Isoxazole Inhibitors of Bromodomains. Paper Presented at: RSC Advances in Synthesis and Medicinal Chemistry (University of Oxford)), C646, C375, C146 (see, e.g. , Chemistry & Biology 2010, 17, All), epigallocatechol gallate (EGCG) (see, e.g. , Cancer Lett. 1998, 14; 130 (1-2), 1-7), garcinol (see, e.g. , PLoS One 2011, 6(9), e24298), I-CBP112 (**see, e.g. , Cancer Res 2015 75 5106-5119), ISOX-DUAL, PF- CBP1 (see, e.g. , Chemistry & Biology 2015 22 1588-1596), L002 (see, e.g. , Mol Cancer Ther 2013, 12(5), 610-620), LTK-14 (see, e.g. , Chemistry & Biology 2007, 14, 605), and PU141 (see, e.g. , Oncogenesis 2015, 4, el37), or combinations thereof.

[9] CBP/p300 activity may be inhibited by blocking catalytic activity or through protein/protein interactions. CBP/p300 has multiple domains including the CBP KIX, C/Hl and C/H3 domains. Those domains may be blocked by an inhibitor such as L001 which inhibits CBP KIX domain (see, e.g. , "Protein Lysine Acetylation by p300/CBP" Dancy & Cole Chem. Rev. 2015 115(6) 2419-2452 and in "KATS in cancer: function and therapies" Farria, Li, and Dent Oncogene 2015 34, 4901-4913).

[10] In another embodiment, the present disclosure provides a method of inducing apoptosis in a cancer cell comprises administering to the cancer cell one or more of a kinase inhibitor in combination with one or more of a P-TEFb inhibitor. In some embodiments, the administration of one or more of a kinase inhibitor in combination with one or more of a P-TEFb inhibitor to the cancer cells can comprise contacting the cancer cell with one or more of a kinase inhibitor and one or more of a P-TEFb inhibitor. In some embodiments, the P-TEFb inhibitor is a BRD4 inhibitor. In some embodiments, the BRD4 inhibitors can include, but are not limited to apabetalone, BI2536, bromosporine, CPI-203, I-BET151, 1-BET762, JQ1, MS436, OTX015, PF-431396, PFI-1, TG-101209, and TG-101348, or combinations thereof.

[11] In another embodiment, the present disclosure provides a method of inducing apoptosis in a cancer cell comprises administering to the cancer cell one or more of a kinase inhibitor in combination with one or more of a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor. In some embodiments, the administration of one or more of a kinase inhibitor in combination with one or more of a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor, to the cancer cells can comprise contacting the cancer cell with one or more of a kinase inhibitor and one or more of a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor. In some embodiments, the one or more CBP inhibitor, the p300 inhibitor, and/or the CBP/p300 inhibitor, can include, but are not limited to SGC-CBP30, BDOIA383, C646, C375, C146, epigallocatechol gallate (EGCG), I-CBP112, ISOX-DUAL, garcinol, L002, LTK-14, PF-CBP1 and PU141, or combinations thereof.

[12] In one embodiment, the present disclosure provides a method for inhibiting growth of a cancer cell which comprises administering to the cancer cell one or more of a kinase inhibitor in combination with one or more of a P-TEFb inhibitor, wherein the one or more P-TEFb inhibitor is a CDK9 (cyclin-dependent kinase 9) inhibitor and it is administered in an effective amount to prevent kinome reorganization and substantial resistance of the cancer cell to the kinase inhibitor. In some embodiments, the CDK9 inhibitor can include, but are not limited to AT7519 (see, e.g., Santo et al., Oncogene (2010) 29(16): 2325-36), AZD5438 (see, e.g. , Byth et al., Mol Cancer Ther (2009); 8(7): 1856-66), CYC065 (see, e.g. , Scaltriti et al., Proc Natl Acad Sci USA (2011); 108(9): 3761-3766), CYC202 (see, e.g., Atanasova et al., Biochem Pharmacol (2005); 70(6): 824-36), dinaciclib (see, e.g., Gojo et al., Cancer Chemother Pharmacol (2013); 72(4): 897-908), EXEL3700 (see, e.g. , EP2747755 Al), EXEL8647 (see, e.g., EP2561867 Al), flavopiridol (see, e.g. , Carlson et al., Cancer Res (1996) 56; 2973), HMR1275 (see, e.g., Carlson, supra), HY-15878 (see, e.g. , Albert et al., Br J Pharmacol (2014); 171(1): 55-68), HY-16462 (CAS No. 1263369-28-3), LDC000067 (see, e.g., Albert et al., supra), MK7965 (see, e.g., Stephenson et al., Lung Cancer (2014); 83(2): 219-23), NVP1 (see, e.g. , Wang et al., Acta Biochim Biophys Sin (2008) 40 (11): 970-978), NVP2 (see, e.g., Sutton, J. C. (2014) Selective CDK9 inhibitors: Stories in lead optimization and toxicology. Novartis Institutes of Biomedical Research, Emeryville, CA. AACR April 2014, San Diego, CA), ON108600 (see, e.g. , Padgaonkar, Amol, Doctoral Dissertation, Discovery, Biological and Structural Characterization of ONI 08600, a Novel Kinase Inhibitor in Triple Negative Breast Cancer (2014), Department of Molecular Biology and Genetics, Temple University Libraries), P276-00 (see, e.g. , Shirsath et al., Mol Cancer. (2012); 11: 77), PHA-767491 (see, e.g., Natoni et al., Mol Cancer Ther (2011); 10(9): 1624-34, PTEFb-BAYl (see, e.g., Poster Session: Experimental and Molecular Therapeutics 32: Cell Cycle andPI3K/AKT Inhibitors; Presentation# 4538 "PTEFb-BAYl, a highly selective, potent and orally available inhibitor of PTEFb/CDK9, shows convincing anti-tumor activity", Poster section 30, Poster# 24 AACR April 2014, San Diego, CA), Roscovitine (see, e.g. , Maurer et al., J Cell Biochem (2011 Mar); 112(3): 761-72), SEL120 (see, e.g. , Safuwan et al., European Journal of Cancer (48), Supp. 6, 160 (2012), and SNS032 (see, e.g. , Chen et al., Blood (2009); 113(19): 4637-45), or combinations thereof.

[13] In other embodiments, the one or more P-TEFb inhibitor may be an inhibitor of another protein that associates in a complex with P-TEFb-CDK9/Cyclin T such as a HEXIM inhibitor, a JMJD6 inhibitor or an NSD3inhibitor.

[14] In one embodiment, the present disclosure provides a method for inhibiting growth of a cancer cell which comprises administering to the cancer cell a one or more of kinase inhibitor in combination with one or more of a P-TEFb inhibitor, wherein the one or more P-TEFb inhibitor is administered in an effective amount to prevent kinome reorganization and substantial resistance of the cancer cell to the kinase inhibitor. In some embodiments, the one or more kinase inhibitor is selected from the group consisting of a lipid kinase inhibitor, a mitogen-activated protein kinase (MAPK) inhibitor, non-receptor tyrosine kinase inhibitor, a receptor tyrosine kinase (RTK) inhibitor, and a serine/threonine kinase inhibitor, or combinations thereof.

[15] In one embodiment, the present disclosure provides a method for inhibiting growth of a cancer cell which comprises administering to the cancer cell a one or more of kinase inhibitor in combination with one or more of a P-TEFb inhibitor, wherein one or more kinase inhibitor is a lipid kinase inhibitor and wherein the one or more P-TEFb inhibitor is administered in an effective amount to prevent kinome reorganization and substantial resistance of the cancer cell to the kinase inhibitor. In some embodiments, the lipid kinase inhibitor can include, but is not limited to, phosphoinositide 3 -kinase, (PI3K) inhibitor, phosphoinositide 4-kinase (PI4K) inhibitor, and Vps34 (a component of a subgroup of PI3K known as class III PI3K) inhibitor, or combinations thereof.

[16] In one embodiment, the present disclosure provides a method for inhibiting growth of a cancer cell which comprises administering to the cancer cell a one or more of kinase inhibitor in combination with one or more of a P-TEFb inhibitor, wherein the one or more kinase inhibitor is a MAPK inhibitor and wherein the one or more P-TEFb inhibitor is administered in an effective amount to prevent kinome reorganization and substantial resistance of the cancer cell to the kinase inhibitor. In some embodiments, the MAPK inhibitor can include, but is not limited to, ARAF (an enzyme, in humans, encoded by the ARAF gene) inhibitor, a BRAF (an enzyme, in humans, encoded by the BRAF gene) inhibitor, a CRAF (an enzyme, in humans, encoded by the RAFl gene) inhibitor, and a MEK inhibitor (a compound that inhibits MAPK enzymes MEK1 and/or MEK2 which are an enzyme, in humans, encoded by the MAP2K1 gene and MAP2K2 gene, respectively), or combinations thereof.

[17] In one embodiment, the present disclosure provides a method for inhibiting growth of a cancer cell which comprises administering to the cancer cell one or more of a MAPK inhibitor in combination with one or more of a P-TEFb inhibitor, wherein the one or more MAPK inhibitor is a BRAF inhibitor and wherein the one or more P-TEFb inhibitor is administered in an effective amount to prevent kinome reorganization and substantial resistance of the cancer cell to the kinase inhibitor. In some embodiments, the BRAF inhibitor can include, but is not limited to, ARQ736, AZ628, AZD8055, BEZ235, cetuximab, dabrafenib, dacarbazine, erlotinib, everolimus, GDC-0879, GDC-0941, gefitinib, GSK2118436, imatinib, LGX818, PLX-4720, RAF265, RO5212054, SAR245409, SAR2455408, sorafenib, temsirolimus, tomozolomide, vemurafenib, and XL281, or combinations thereof.

[18] In one embodiment, the present disclosure provides a method for inhibiting growth of a cancer cell which comprises administering to the cancer cell one or more of a MAPK inhibitor in combination with one or more of a P-TEFb inhibitor, wherein the one or more MAPK inhibitor is a MEK inhibitor and wherein the one or more P-TEFb inhibitor is administered in an effective amount to prevent kinome reorganization and substantial resistance of the cancer cell to the kinase inhibitor. In some embodiments, the MEK inhibitor can include, but is not limited to ARRY438162, AZD6244, binimetinib, CI- 1040, GDC0941, GDC0973, MEK162, PD035901, PD318088, PD334581, PD98059, pimasertib, R05126766, RDEA119, RDEA436, selumetinib, TAK733, trametinib, and XL518, or combinations thereof.

[19] In one embodiment, the present disclosure provides a method for inhibiting growth of a cancer cell which comprises administering to the cancer cell one or more of a kinase inhibitor in combination with one or more of a P-TEFb inhibitor, wherein the one or more kinase inhibitor is a non-receptor tyrosine kinase inhibitor and wherein the one or more P-TEFb inhibitor is administered in an effective amount to prevent kinome reorganization and substantial resistance of the cancer cell to the kinase inhibitor. In some embodiments, the nonreceptor tyrosine kinase inhibitor can include, but is not limited to Abl (Abelson or a protein, in humans, encoded by the ABL1 gene) inhibitor, a BTK (Bruton's tyrosine kinase) inhibitor, a Jak (Janus kinase) inhibitor, and a Src (Sarcoma kinase) inhibitor, or combinations thereof. In a further embodiment, the non-receptor tyrosine kinase inhibitor is selected from a group consisting of bosutinib, dasatinib, ibrutinib, imatinib, KX2-391, LFM-A13, nilotinib, pacritinib, PF-573228, ponatinib, ruxolitinib, saracatinib, and tofacitinib, or combinations thereof. [20] In one embodiment, the present disclosure provides a method for inhibiting growth of a cancer cell which comprises administering to the cancer cell one or more of a kinase inhibitor in combination with one or more of a P-TEFb inhibitor, wherein the one or more kinase inhibitor is a RTK inhibitor and wherein the one or more P-TEFb inhibitor is administered in an effective amount to prevent kinome reorganization and substantial resistance of the cancer cell to the kinase inhibitor. In some embodiments, the RTK inhibitor can include, but is not limited to, anaplastic lymphoma kinase (ALK) inhibitor, a c-MET (hepatocyte growth factor receptor) inhibitor, an EGFR (epidermal growth factor receptor) inhibitor, an ERBB (human epidermal growth factor receptor) inhibitor, a FGF (fibroblast growth factor) inhibitor, a PDGF (platelet-derived growth factor) inhibitor and a VEGF (vascular endothelial growth factor) inhibitor, or combinations thereof. In a further embodiment, the RTK inhibitor is selected from a group consisting of afatinib, alectinib (CH5424802)*, AP26113 (Ariad)*, ASP3026 (Astellas US 8,318,702), axitinib, cabozantinib, cediranib, CEP-37440 (Teva)*, ceritinib (LDK378)*, cetuximab, EBI215 (Eternity), entrectinib (RXDX101, Nervano US 8,299,057), erlotinib, foretinib, gefitinib, gilteritinib (ASP2215 US 8,969,336), grandinin, lapatinib, neratinib, panitumumab, pazopanib, pazopanib, PF-06463922 (Pfizer)*, quizartinib, regorafenib, semaxanib, sorafenib, sunitinib, tivantinib, tivoaznib, toceranib, trastuzumab, TSR-011 (Tesaro), vandetanib, and X-396 (Xcovery) or combinations thereof. Commercially available from MedChem Express (Monmouth Junction, NJ, USA).

[21] In one embodiment, the present disclosure provides a method for inhibiting growth of a cancer cell which comprises administering to the cancer cell one or more of a kinase inhibitor in combination with one or more of a P-TEFb inhibitor, wherein the one or more kinase inhibitor is a serine/threonine kinase inhibitor and wherein the one or more P-TEFb inhibitor is administered in an effective amount to prevent kinome reorganization and substantial resistance of the cancer cell to the kinase inhibitor. In some embodiments, the serine/threonine kinase inhibitor can include, but is not limited to, enzastaurin, H-7, LY294002, sorafenib, and staurosporine, or combinations thereof.

[22] In one embodiment, the present disclosure provides a method for inhibiting growth of a cancer cell which comprises administering to the cancer cell one or more of a positive transcription elongation factor b (P-TEFb) inhibitor in combination with one or more of a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor, wherein the one or more P-TEFb inhibitor and one or more of the CBP inhibitor, the p300 inhibitor, and/or the CBP/p300 inhibitor is administered in an effective amount to prevent kinome reorganization.

[23] In some embodiments, the administration of one or more of a P-TEFb inhibitor in combination with one or more of a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor to the cancer cells can comprise contacting the cancer cell with one or more of a P-TEFb inhibitor and one or more of a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor. As used herein, one or more of a P-TEFb inhibitor may be an inhibitor that modulates or interferes with the pause/elongation function of RNA polymerase II of P-TEFb that is CDK9/cyclin T and its complex with BRD4, JMJD6 and NSD3. In some embodiments, the one or more P-TEFb inhibitor is a BRD4 (BET family bromodomain-containing protein 4) inhibitor. As used herein, one or more of a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor may be an inhibitor that modulates the acetylation of histones, such that BET bromodomain activity (e.g., BRD4), is reduced or modulated in a way that interferes with the pause/elongation function of RNA polymerase II of P-TEFb downstream.

[24] In one embodiment, the present disclosure provides a method for inhibiting growth of a cancer cell which comprises administering to the cancer cell one or more of a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor in combination with one or more of a chemotherapeutic compound, wherein the one or more of the CBP inhibitor, the p300 inhibitor, and/or the CBP/p300 inhibitor and the one or more chemotherapeutic compound is administered in an effective amount to prevent kinome reorganization and substantial resistance of the cancer cell to the kinase inhibitor. In one embodiment, the one or more chemotherapeutic compound is not a kinase inhibitor. In another embodiment, the one or more chemotherapeutic compound is a nucleotide analog or precursor analog thereof. In one embodiment, the nucleotide analog or precursor analog thereof is selected from the group consisting of azacitidine, azathioprine, capecitabine, cytarabine, doxifluridine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, and tioguanine. In one embodiment, the nucleotide analog or precursor analog thereof is gemcitabine. In addition, combinations may be used such as (i) gemcitabine, a p300 inhibitor and a pTEF-b inhibitor; (ii) gemcitabine, a kinase inhibitor and p300 inhibitor; or (iii) gemcitabine, a kinase inhibitor and a pTEF-b inhibitor.

[25] In another embodiment, the present disclosure provides a method of inducing apoptosis in a cancer cell comprises administering to the cancer cell one or more of a P-TEFb inhibitor in combination with one or more of a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor. In some embodiments, the administration of one or more of a P-TEFb inhibitor and one or more of a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor to the cancer cells can comprise contacting the cancer cell with one or more of a P-TEFb inhibitor and one or more of a CBP/p300 inhibitor.

[26] In one embodiment, the present disclosure provides a method of inducing apoptosis in a cancer cell comprising administering to the cancer cell one or more of a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor in combination with a chemotherapeutic compound. In one embodiment, the chemotherapeutic compound is a nucleotide analog or precursor analog thereof. In some embodiments, the administration of one or more of a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor and the chemotherapeutic compound to the cancer cells can comprise contacting the cancer cell with a CBP/p300 inhibitor and a chemotherapeutic compound.

[27] In one embodiment, the present disclosure provides a method for inhibiting growth of a cancer cell which comprises administering to the cancer cell one or more of a kinase inhibitor in combination with one or more of a positive transcription elongation factor b (P-TEFb) inhibitor and one or more of a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor, wherein the kinase inhibitor and the P-TEFb inhibitor and the CBP inhibitor, the p300 inhibitor, and/or the CBP/p300 inhibitor is administered in an effective amount to prevent kinome reorganization and the development of resistance of the cancer cell to the kinase inhibitor.

[28] In some embodiments, the administration of one or more of a kinase inhibitor in combination with one or more of a P-TEFb inhibitor and one or more of a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor to the cancer cells can comprise contacting the cancer cell with a kinase inhibitor and a P-TEFb inhibitor with a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor.

[29] In another embodiment, the present disclosure provides a method of inducing apoptosis in a cancer cell comprises administering to the cancer cell one or more of a kinase inhibitor in combination with one or more of a P-TEFb inhibitor and one or more of a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor. In some embodiments, the administration of one or more of a kinase inhibitor in combination with one or more of a P-TEFb inhibitor and one or more of a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor to the cancer cells can comprise contacting the cancer cell with one or more of a kinase inhibitor and one or more of a P-TEFb inhibitor along with one or more of a CBP inhibitor, a p300 inhibitor, and/or a CBP/p300 inhibitor.

[30] In one embodiment, the present disclosure relates to a method of treating a subject with a cancer driven by dysregulation of a kinase signaling network or a RAS (rat sarcoma) oncogene by (i) administering to the subject one or more of a compound that inhibits the activity of a kinase and (ii) administering to the subject one or more of a compound that inhibits the activity of P-TEFb and/or one or more of a compound that inhibits the activity of CBP and/or p300. In some embodiments, the one or more compound that inhibits the activity of a kinase and the one or more compound that inhibits the activity of P-TEFb and/or the one or more compound that inhibits the activity of CBP and/or p300 are administered simultaneously. In another embodiment, the one or more compound that inhibits the activity of a kinase and the one or more compound that inhibits the activity of P-TEFb and/or the one or more compound that inhibits the activity of CBP and/or p300 are administered sequentially.

[31] In one embodiment, the present disclosure relates to a method of reducing the proliferation rate of a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene by (i) administering to the subject one or more of a compound that inhibits the activity of a kinase and (ii) administering to the subject one or more of a compound that inhibits the activity of P-TEFb and/or one or more of a compound that inhibits the activity of CBP and/or p300.

[32] In another embodiment, the present disclosure relates to a method of enhancing the rate of apoptosis in a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene, by (i) administering to the subject one or more of a compound that inhibits the activity of a kinase and (ii) administering to the subject one or more of a compound that inhibits the activity of P-TEFb and/or one or more of a compound that inhibits the activity of CBP and/or p300.

[33] In one embodiment, the present disclosure relates to a method of treating a subject with a cancer driven by dysregulation of a kinase signaling network or a RAS (rat sarcoma) oncogene by (i) administering to the subject one or more of a compound that inhibits the activity of a P-TEFb and (ii) administering to the subject one or more of a compound that inhibits the activity of CBP and/or p300. In some embodiments, the one or more compound that inhibits the activity of a P-TEFb and the one or more compound that inhibits the activity of CBP and/or p300 are administered simultaneously. In another embodiment, the one or more compound that inhibits the activity of a P-TEFb and the one or more compound that inhibits the activity of CBP and/or p300 are administered sequentially.

[34] In one embodiment, the present disclosure relates to a method of reducing the proliferation rate of a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene by (i) administering to the subject one or more of a compound that inhibits the activity of a P-TEFb and (ii) administering to the subject one or more of a compound that inhibits the activity of CBP and/or p300.

[35] In another embodiment, the present disclosure relates to a method of enhancing the rate of apoptosis in a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene, by (i) administering to the cancer cell population one or more of a compound that inhibits the activity of a P-TEFb and (ii) administering to the cancer cell population one or more of a compound that inhibits the activity of CBP and/or p300.

[36] In one embodiment, the present disclosure relates to a method of treating a subject with a cancer driven by dysregulation of a kinase signaling network or a RAS (rat sarcoma) oncogene by (i) administering to the subject one or more of a compound that inhibits the activity of CBP and/or p300 and (ii) administering to the subject one or more of a chemotherapeutic compound. In one embodiment, the one or more chemotherapeutic compound is a nucleotide analog or precursor analog thereof. In some embodiments, the one or more compound that inhibits the activity of CBP and/or p300 and the one or more chemotherapeutic compound are administered simultaneously. In another embodiment, the one or more compound that inhibits the activity of CBP and/or p300 and the one or more chemotherapeutic compound are administered sequentially. [37] In one embodiment, the present disclosure relates to a method of reducing the proliferation rate of a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene by (i) administering to the cancer cell population one or more of a compound that inhibits the activity of CBP and/or p300 and (ii) administering to the cancer cell population one or more of a chemotherapeutic compound. In one embodiment, the one or more chemotherapeutic compound is a nucleotide analog or precursor analog thereof. In one embodiment the nucleotide analog or precursor analog thereof is gemcitabine.

[38] In another embodiment, the present disclosure relates to a method of enhancing the rate of apoptosis in a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene, by (i) administering to the cancer cell population one or more of a compound that inhibits the activity of CBP and/or p300 and (ii) administering to the cancer cell population one or more of a chemotherapeutic compound, wherein said chemotherapeutic compound. In one embodiment, the one or more chemotherapeutic compound is a nucleotide analog or precursor analog thereof. In one embodiment the nucleotide analog or precursor analog thereof is gemcitabine.

[39] In one embodiment, the present disclosure relates to a method of treating a subject with a cancer driven by dysregulation of a kinase signaling network or a RAS (rat sarcoma) oncogene by (i) administering to the subject one or more of a compound that inhibits the activity of a kinase, (ii) administering to the subject one or more of a compound that inhibits the activity of a P-TEFb and (iii) administering to the subject one or more of a compound that inhibits the activity of CBP and/or p300. In some embodiments, the one or more compound that inhibits the activity of a kinase, the one or more compound that inhibits the activity of a P- TEFb and the one or more compound that inhibits the activity of CBP and/or p300 are administered simultaneously. In another embodiment, the one or more compound that inhibits the activity of a kinase, the one or more compound that inhibits the activity of a P-TEFb and the one or more compound that inhibits the activity of CBP and/or p300 are administered sequentially in any order.

[40] In one embodiment, the present disclosure relates to a method of reducing the proliferation rate of a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene by (i) administering to the cancer cell population one or more of a compound that inhibits the activity of a kinase, (ii) administering to the cancer cell population one or more of a compound that inhibits the activity of a P-TEFb and (iii) administering to the cancer cell population one or more of a compound that inhibits the activity of CBP and/or p300.

[41] In another embodiment, the present disclosure relates to a method of enhancing the rate of apoptosis in a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene, by (i) administering to the cancer cell population one or more of a compound that inhibits the activity of a kinase, (ii) administering to the cancer cell population one or more of a compound that inhibits the activity of a P-TEFb and (iii) administering to the cancer cell population one or more of a compound that inhibits the activity of CBP and/or p300.

[42] In one embodiment, the cancer cells to be treated with the methods disclosed herein are blood-borne cancer cells. In some embodiments, the blood-borne cancer cells can include, but are not limited to, cells of AML, CML, a hematopoietic system cancer, lymphatic system, and lymphoma.

[43] In one embodiment, the cancer cells to be treated with the methods disclosed herein are solid cancer cells. In some embodiments, the solid cancer cells can include, but are not limited to, cancer cells of bladder, bone, brain, colon, colorectal, ERBB2 (human epidermal growth factor receptor 2)-positive breast, gastric, gastrointestinal, genitourinary tract, glioma, head and neck, larynx, lung, lymphoma, melanoma, non-small cell lung, ovarian, ovary, pancreatic cancer, prostate, small cell lung, stomach, and triple negative breast.

BRIEF DESCRIPTION OF THE FIGURES

[44] FIG. 1 is a bar graph presenting the MIB/MS binding profile of MEK-ERK pathway kinases from trametinib-treated patient tumors. The bar graph shows iTRAQ-determined quantitative changes in MIB binding as a ratio of MEK inhibitor treated and untreated patient tumor.

[45] FIG. 2 illustrates kinome reprogramming in response to MEK inhibitor, trametinib, alone or in combination with BET bromodomain inhibitor, JQ1 or I-BET151, in TNBC CL and BL cell lines for 48 hours.

[46] FIG. 3 illustrates kinome reprogramming in response to MEK inhibitor, trametinib, alone or in combination with BET bromodomain inhibitor, JQ1, in TNBC CL and BL cell lines for 4 weeks.

[47] FIG. 4 illustrates that the P-TEFb-CDK9/Cyclin T associates in a complex that is composed of BRD4, JMJD6, and NSD3. P-TEFb regulates the pause/elongation function of RNA polymerase II and is required for the synthesis of newly induced genes such as RTKs (PDGFRa and DDR1) in the adaptive kinome reprogramming response to targeted kinase inhibition.

[48] FIG. 5 illustrates knockdown of CDK9 inhibits adaptive reprogramming in response to the MEKi trametinib. (A) Basal-like TNBC SUM149PT cells were used for knockdown of the P-TEFb members BRD4 and CDK9. Cyclin-dependent transcriptional CDKs 7 and 8 were also knocked down as controls. Loss of CDK9 was more effective in inhibiting induction of FGFR2 and DDR1 than BRD4, CDK7 or CDK8. (B) Claudin-low TNBC SUM159PT cells were used to knockdown CDK9. Loss of CDK9 effectively inhibited induction of PDGFRa and DDR1. [49] FIG. 6. illustrates that the inhibition of CDK9 blocks trametinib induced reprogramming in TNBC. (A) CDK9 inhibitor (HY16462) prevents MEK inhibitor (trametinib-GSK212) induced up-regulation of PDGFRB and DDR1. CDK9i = 10 nM (+); 100 nM (++) or lOOOnM (+++); trametinib (10 nM). PDGFRB and DDR2 protein determined by Western blotting.

[50] FIG. 7. illustrates dose-dependent inhibition of CDK9 by HY16462. Shown are the results of CDK9 kinase activity (Promega- ADP-Glo) assayed in the presence of increasing concentrations of the CDK9i HY 16462 (HY).

[51] FIG. 8. illustrates that CDK9 inhibition depletes MCLl from cells. PANC- 1 cells were treated with carrier (DMSO), 10 μΜ Gemcitabine or 1 μΜ HY16462 for 24 hr. MCLl determined by Western blotting.

[52] FIG. 9. illustrates SUM159wt cell viability assay dose response results for MEK inhibitor Trametinib and ±100 nM BET bromodomain inhibitor JQ1

[53] FIG. 10. illustrates SUM159R cell viability assay dose response results for MEK inhibitor Trametinib and ±100 nM BET bromodomain inhibitor JQ1 (72 hours).

[54] FIG. 11. illustrates SUM159R cell viability assay dose response results for MEK inhibitor Trametinib and ±100 nM BET bromodomain inhibitor JQ1 (7 days).

[55] FIG. 12. illustrates SUM159wt cell viability assay dose response results for MEK inhibitor Trametinib and ±10 μΜ CBP/p300 inhibitor SGC-CBP30.

[56] FIG. 13. illustrates SUM159wt cell viability assay dose response results for CBP/p300 inhibitor SGC-CBP30 and ±100 nM BET bromodomain inhibitor JQ1.

[57] FIG. 14. illustrates SUM159wt cell viability assay dose response results for BET bromodomain inhibitor JQ1 and ±10 μΜ CBP/p300 inhibitor SGC-CBP30.

[58] FIG. 15. illustrates H385 non-small cell lung cancer cell viability assay dose response results for MEK inhibitor Trametinib and ±10 μΜ CBP/p300 inhibitor SGC-CBP30. [59] FIG. 16. illustrates PANC1 human pancreatic carcinoma cell viability assay dose response results for chemotherapeutic compound Gemcitabine with ±10 μΜ CBP/p300 inhibitor SGC-CBP30.

[60] FIG. 17. Illustrates SKBR3 human Her2-positive breast cancer cell viability assay dose response results for EGFR and ErbB2 inhibitor Lapatinib with ±10 μΜ CBP/p300 inhibitor SGC-CBP30.

DETAILED DESCRIPTION

Definitions

[61] While the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter.

[62] Throughout the present specification, the terms "about" and/or "approximately" may be used in conjunction with numerical values and/or ranges. The term "about" is understood to mean those values near to a recited value. For example, "about 40 [units]" may mean within ± 25% of 40 {e.g. , from 30 to 50), within ± 20%, ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, ± 1%, less than ± 1%, or any other value or range of values therein or therebelow. Furthermore, the phrases "less than about [a value]" or "greater than about [a value]" should be understood in view of the definition of the term "about" provided herein. The terms "about" and "approximately" may be used interchangeably.

[63] Throughout the present specification, numerical ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range "from 50 to 80" includes all possible ranges therein (e.g. , 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g. , the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.). [64] The term "a" or "an" refers to one or more of that entity; for example, "a kinase inhibitor" refers to one or more kinase inhibitors or at least one kinase inhibitor. As such, the terms "a" (or "an"), "one or more" and "at least one" are used interchangeably herein. In addition, reference to "an inhibitor" by the indefinite article "a" or "an" does not exclude the possibility that more than one of the inhibitors is present, unless the context clearly requires that there is one and only one of the inhibitors.

[65] As used herein, the verb "comprise" as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. The present invention may suitably "comprise", "consist of, or "consist essentially of, the steps, elements, and/or reagents described in the claims.

[66] It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely", "only" and the like in connection with the recitation of claim elements, or the use of a "negative" limitation.

[67] As used herein, the term "inhibitor" refers to an agent that inhibits the normal cellular activities of the proteins that are involved, that constitute, or that are participants in the cellular pathways.

[68] As used herein, the term "cancer" refers to a condition where one or more mammalian cells which are growing or have grown in an uncontrolled manner to form cancer tissue. Cancers include solid cancers and blood borne cancers. The term "cancer cell" or "cancer cell line" refers to cells or cell lines of the cancer described above. The term "cancer" and "tumor" can be used interchangeably.

[69] The term "treat," "treated," "treating" or "treatment" includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated. Treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder or a disease.

[70] As used herein, the term "apoptosis" refers to the process of programmed cell death, with its accompanying cellular morphological changes and loss of cell viability. This does not mean that all methods of inducing apoptosis or the mechanisms of cell death associated with different induction methods are the same. In other words, apoptosis refers to a regulated network of biochemical events which lead to a selective form of cell suicide, and is characterized by readily observable morphological and biochemical phenomena, such phenomena include but are not limited to the fragmentation of the deoxyribonucleic acid (DNA), condensation of the chromatin, which may or may not be associated with endonuclease activity, chromosome migration, margination in cell nuclei, the formation of apoptotic bodies, mitochondrial swelling, widening of the mitochondrial cristae, opening of the mitochondrial permeability transition pores and/or dissipation of the mitochondrial proton gradient.

[71] As used herein, the term "resistance" refers to reduction in the effectiveness of a drug, such as kinase inhibitors, in treating a disease or a condition.

[72] As used herein, the term "kinome" refers the set of protein kinases in an organism's genome.

[73] As used herein, the term "kinase" refers to a class of enzymes that catalyzes phosphorylation.

[74] As used herein, the term "subject," "individual" or "patient" is used interchangeably and refers to a vertebrate, preferably a mammal. Non-limiting examples include mice, dogs, rabbits, farm animals, sport animals, pets, and humans.

[75] As used herein, "therapeutically effective amount" or an "effective amount" indicates an amount that results in a desired pharmacological and/or physiological effect for the condition. The effect may be prophylactic in terms of completely or partially preventing a condition or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for the condition and/or adverse effect attributable to the condition.

[76] As used herein, the terms "synergy" or "synergistic effect" means that the therapeutic effect of the compounds, therapeutics, or drugs when used in combination is greater than the additive therapeutic effects of the compounds when used individually. In one example, a synergy between compounds X and Y is observed when the combination of the two compounds reduces cell proliferation by 80% whereas compound X alone only reduces cell proliferation by 20% and compound Y alone only reduces cell proliferation by 15%. The 80% reduction in cell proliferation exceeds the expected additive effect of 35%; thus, compounds X and Y show synergistic effect for reducing cell proliferation.

[77] As used herein, "specific" with respect to an inhibitor of a particular target means that the inhibitor exhibits a lack of promiscuity and binds to the target with a certain degree of specificity relative to other possible targets. For example, a specific BRD4 inhibitor can bind to BRD4 preferentially relative to one or more possible binding targets with a relative binding specificity ratio of, e.g., about 2: 1, about 3: 1, about 4: 1, about 5: 1, about 6: 1, about 7: 1, about 8: 1, about 9: 1, about 10:1, about 15: 1, about 20: 1, about 30: 1, about 40: 1, about 50: 1, about 60: 1, about 70: 1, about 80: 1, about 90: 1, about 100: 1, about 150: 1, about 200: 1, about 500: 1, about 10³ : 1 , about 10⁴: 1 , or greater, or any other value or range of values therein. Alternatively, a specific inhibitor may bind to only one enzyme with an IC50 of less than 100 nM, less than five enzymes with an IC50 of less than 200 nM, more preferably only one enzyme with an IC50 of less than 100 nM. Furthermore, the relative binding specificity of the inhibitor of a particular target relative to each possible alternative binding target is independent. Thus, for example, a BRD4 or a CDK9 inhibitor can bind preferentially to BRD4 relative to a first protein at a ratio of about 10: 1, and can bind preferentially to BRD4 relative to a second protein at a ratio of about 40: 1. [78] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Preferred methods, devices, and materials are described, although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All references cited herein are incorporated by reference in their entirety.

Protein Kinase

[79] A protein kinase is a kinase enzyme that facilitates phosphorylation of a targeted protein, which results in functional change of the targeted protein. It is estimated that approximately one third of all proteins present in a mammalian cell are phosphorylated and that kinases constitute about 1-3% of the expressed genome. Dysregulation of kinase activity is a frequent cause of many diseases, including cancer, because kinases regulate cellular signaling pathways such as those responsible for cell growth. One class of kinases that are frequently deregulated in cancer cells is receptor tyrosine kinases (RTKs).

[80] RTKs are a subclass of protein kinase which, in general, have an extracellular binding domain, a transmembrane domain, and an intracellular kinase domain. Ligand binding through the RTK's extracellular domain causes RTK monomers to form dimers. The dimerization of RTKs induces autophosphorylation of tyrosine residues which in turn activates downstream phosphorylation signaling cascades (e.g., Ras pathway, mitogen- activated protein kinase (MAPK) signaling cascade).

[81] In order to regulate kinase activity in cancer cells, kinase inhibitors have been studied and used for the treatment of cancer; however, one major drawback has been resistance development. Kinase inhibitors that are approved by the U.S. Food and Drug Administration (FDA) include afatinib, axitinib, bosutinib, cabozanitinib, ceritinib, crizotinib, dabrafenib, dasatinib, erlotinib, everolimus, gefitinib, ibrutinib, imatinib, lapatinib, nilotinib, nintedanib, pazopanib, ponatinib, regorafenib, ruxolitinib, sirolimus, sorafenib, tofacitinib, temsirolimus, trametinib, vandetanib, and vemurafenib. These various kinase inhibitors target different kinases such as non-receptor tyrosine kinases and receptor tyrosine kinases as well as different sites on a kinase including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor, proto-oncogene B-Raf (BRAF), and hepatocyte growth factor receptor.

Resistance to Kinase Inhibitors

[82] Single target kinase inhibitors generally fail to sustain durable responses when used to treat a range of human cancers. The reasons for resistance can include mutations in the target kinase, amplification of the downstream Ras pathways including mutations in the downstream kinase sites, and kinome reprogramming, a process where system-wide changes occur in kinase networks. Such kinase reprogramming effectively bypasses the inhibited kinase via reconfiguration of signaling pathways downstream of the inhibited kinase, such that it is no longer necessary for the inhibited kinase to trigger a process, for example, leading to cell proliferation. Instead, a different kinase takes over the role of the inhibited kinase in the reconfigured pathway.

[83] Mutation of the targeted kinase may result in inhibiting the binding of the kinase inhibitor completely, or necessitating a higher dose of the kinase inhibitor for a given treatment. Common mutation sites of, e.g., the tyrosine kinase domain include, e.g., EGFR.

[84] One mechanism of resistance to a kinase inhibitor involves upregulation of multiple kinases in downstream signaling pathways. This allows the kinase that is being inhibited to be bypassed. For example, MEK inhibitors regulate the MEK1/2 site such that the subsequent ERK1/2 (extracellular- signal-regulated kinases 1/2) phosphorylation and activation is lost (MEK-ERK pathway), resulting in MEK-ERK pathway inhibition. However, the inhibition of MEK-ERK pathway could be overcome by upregulation of multiple RTK RNAs, which stimulates downstream signaling pathways. This change in the kinase network is referred to as kinome reprogramming.

Kinome Reprogramming

[85] As described previously, single target kinase inhibitors generally cannot sustain efficacy, and rapid resistance develops. Thus, there is a need for a method of suppressing or inhibiting resistance to kinase inhibitors, such that a single kinase inhibitor can be effectively used as a therapeutic agent, for example, in the treatment of cancer. Without intending to be bound by theory, if the source of kinome reprogramming can be identified and controlled, then the use of single kinase inhibitor could become more effective. Another reason this approach may be superior over the use of multiple kinase inhibitors is because kinase inhibitor mediated upregulation of other RTKs varies widely between patients and also as a function of different kinase inhibitors employed.

[86] One method that can be used to identify the effect of kinome reprogramming on the kinome activity profile is to use multiplexed inhibitor beads coupled with mass spectrometry (MIB/MS) to quantitatively measure dynamic changes in kinase activity on proteomic scale and compare the untreated cell to cells treated with a kinase inhibitor. MIBs are beads in which different kinase inhibitors are immobilized through linker adaptors. The immobilized inhibitors are primarily type I kinase inhibitors that preferentially bind activated kinase (versus inactive). Kinase capture is highly reproducible and is a function of kinase affinity for different immobilized inhibitors as well as the kinase activation state. By coupling MIB capture with mass spectrometry (MIB/MS), the technique allows quantitative interrogation of a large number of kinases in a single mass spectrometry run. This also interrogates kinases known by sequence but which have been understudied due to lack of reagents such as specific phospho- antibodies. [87] MIB/MS study can be conducted with various cancer cells and those treated with a wide number of kinase inhibitors, such as those listed above as FDA approved kinase inhibitors. For the purpose of observing the blocking of kinome reprogramming, the study described herein and provided in the Examples focuses on MEK inhibitor and tyrosine kinase inhibitor use for breast cancer cells. However, one skilled in the art would realize that this method could be applied to a wide variety of cancer types and kinase inhibitor combinations.

P-TEFb transcriptional elongation complex

[88] P-TEFb plays an important role in coordinating the elongation phase of transcription by regulation of transcription by RNA polymerase II. It is suggested that P-TEFb directs cells towards either proliferation or differentiation; therefore, it has been identified as a key player in kinome reprogramming as described herein. BRD4 is known to interact with cyclin Tl and cyclin-dependent kinase 9 (CDK9) to constitute the core of P-TEFb.

[89] BET family bromodomain proteins, including BRD4, contain a bromodomain and an extraterminal region. Bromodomain proteins are acetyl- lysine readers which bind to acetylated lysine residues in proteins. BET family bromodomain proteins bind at enhancers and promoters of acetylated lysines in histones such as acetylated Lys27 in histone H3 (histone H3 Ack27). BET bromodomain proteins bound to histone H3 Ack27 recruit proteins regulating RNA polymerase II and transcription. Specifically, BRD4 recruits P-TEFb and RNA polymerase II to promoter regions, thereby stimulating kinase activity.

[90] Thus, in one embodiment, inhibition of BET bromodomains would reduce P-TEFb and RNA polymerase II recruitment to promoter regions which in turn reduce or eliminate overstimulation of kinase activity. BET bromodomain inhibitors, such as JQ1 and I-BET151 bind within the acetylated lysine reader domain and prevent binding to the bromodomain encoded protein to acetylated lysines. Known BET bromodomain inhibitors include, but are not limited to, apabetalone, BI2536, Bromosporine, CPI-203, I-BET151, I-BET762, JQ1, MS436, OTX015, PF-431396, PFI-1, TG-101209, and TG-101348.

[91] CDK9 is a member of the serine/threonine kinase family. CDK9 pathway deregulation has been observed in cancer cells and tumors; thus, CDK9 is another important component of P-TEFb that should be considered for the combination therapy with kinase inhibitors for inhibiting the kinome reprogramming. CDK9 is found to function by phosphorylating the C- terminal domain of the largest subunit of RNA polymerase II. CDK9 forms a complex with and is regulated by its regulatory subunit cyclin T or cyclin K. Known CDK9 inhibitors include, but are not limited to, AT7519, AZD5438, CYC065, CYC202, dinaciclib, EXEL3700, EXEL8647, flavopiridol, HMR1275, HY-15878, HY-16462, LDC000067, MK7965, NVP1, NVP2, ON108600, P276-00, PHA-767491, PTEFb-BAYl, Roscovitine, SEL120, and SNS032.

Histone Acetyltransferases (HATs)

[92] As discussed above, BRD4 binds to acetylated lysine residues in histones. In one embodiment, inhibition of certain HATs would reduce or prevent downstream kinase activities. For example, CREBBP (also known as CBP) and EP300 (also known as p300) are two homologous proteins that are histone acetyltransferases which catalyze the transfer of the acetyl moiety from acetyl-CoA to specific lysine residues in histones. CBP and p300 also catalyzes the acetylation of proteins other than histones, thus they are also referred to as lysine acetyltransferases (KATs).

[93] CBP and p300 proteins have a catalytic domain which facilitates the acetyl transfers and also a bromodomain region that is distinct from BET bromodomains. For example, SGC- CBP30 and I-CBP112, developed by the Structural Genomics Consortium, are CBP and p300 inhibitors that bind to the bromodomain regions of CBP and p300. (see, e.g., J. Am. Chem. Soc. 2014 136 9308-9319 and Cancer Res 2015 75 5106-5119). C646, C375, and C146 are CBP/p300 catalytic site inhibitors where C646 is more selective towards p300 inhibition when compared to C146 and C375. Epigallocatechol gallate (EGCG) blocks P300-mediated acetylation. L002 inhibits P300 in vitro and blocks histone and p53 acetylation. BDOAIA383 is a potent CBP inhibitor with modest selectivity over BRD4. ISOX-DUAL is an active compound that binds CBP and BRD4 with similar affinities, PF-CBPl has 139-fold higher affinity for CBP (see, e.g. , Chemistry & Biology 2015 22 1588-1596). Garcinol has been shown to have an inhibitory effect on HATs (see e.g. Frontiers in Oncology 2015, 5, 108). LTK-14 is a garcinol derivative which is a known CBP/p300 inhibitor. PU141, a pyridoisothiazolone INT- benzyl derivative, is a known CBP/p300 inhibitor.

Combination Therapy

[94] In one embodiment, the present disclosure provides a combination therapy which includes at least two components: one or more of a kinase inhibitor (A) and one or more of a P-TEFb inhibitor, a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor (B). A combination therapy of one or more of a kinase inhibitor and one or more of a P-TEFb inhibitor, a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor, in some embodiments, results in the inhibition of cancer cell growth. In another embodiment, the combination therapy of one or more of a kinase inhibitor and one or more of a P-TEFb inhibitor, a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor results in inducing apoptosis in the cancer cell. In one embodiment, the combination therapy increases the potency of the one or more kinase inhibitor and/or the one or more P-TEFb inhibitor compared to the potency when measured by itself (not in a combination). In one embodiment, the combination therapy increases the potency of the one or more kinase inhibitor and/or the one or more CBP inhibitor, the p300 inhibitor and/or the CBP/p300 inhibitor compared to the potency when measured by itself (not in a combination). In another embodiment, the combination therapy provides a therapeutic synergy or positive cooperatively among the one or more kinase inhibitor and the one or more P-TEFb inhibitor, the CBP inhibitor, the p300 inhibitor and/or the CBP/p300 inhibitor to enhance therapeutic potential. In some embodiments, the combination therapy exhibits therapeutic synergy between the one or more kinase inhibitor and one or more of the P-TEFb inhibitor, the CBP inhibitor, the p300 inhibitor and/or the CBP/p300 inhibitor for blocking adaptive kinome reorganization response to the targeted kinase inhibitor.

[95] A combination therapy, in one embodiment, comprises one or more of a BET bromodomain inhibitor as a P-TEFb inhibitor. Further, the BET bromodomain inhibitor can be a BRD4 inhibitor selected from the group consisting of apabetalone, BI2536, bromosporine, CPI-203, I-BET151, 1-BET762, JQ1, MS436, OTX015, PF-431396, PFI-1, TG-101209, and TG-101348, or combinations thereof.

[96] A combination therapy, in another embodiment, comprises one or more of a kinase inhibitor and one or more of a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor. In one embodiment, a combination therapy comprises one or more of a kinase inhibitor and one or more of a CBP inhibitor. In another embodiment, a combination therapy comprises one or more of a kinase inhibitor and one or more of a p300 inhibitor. In some embodiments, a combination therapy comprises one or more of a kinase inhibitor and one or more of a CBP/p300 inhibitor. Non limiting example of one or more of a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor includes SGC-CBP30, BDOIA383, C646, C375, C146, epigallocatechol gallate (EGCG), I-CBP112, ISOX-DUAL, garcinol, L002, LTK-14, PF- CBP1, and PU141, or combinations thereof.

[97] In one embodiment, a combination therapy comprises one or more of a CDK9 inhibitor as a P-TEFb inhibitor. In some embodiments, the one or more CDK9 inhibitor is selected from the group consisting of AT7519, AZD5438, CYC065, CYC202, dinaciclib, EXEL3700, EXEL8647, flavopiridol, HMR1275, HY-15878, HY-16462, LDC000067, MK7965, NVP1, NVP2, ON108600, P276-00, PHA-767491, PTEFb-BAYl, Roscovitine, SEL120, and SNS032, or combinations thereof.

[98] In another embodiment, the present disclosure provides a combination therapy, wherein a single active or a single molecule has the properties of a kinase inhibitor and a P-TEFb inhibitor, a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor.

[99] In one embodiment, the present disclosure provides a combination therapy which includes one or more of a P-TEFb inhibitor and one or more of a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor. A combination therapy of one or more of a P-TEFb inhibitor and one or more of a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor, in some embodiments, results in the inhibition of cancer cell growth. In another embodiment, administering a combination therapy including one or more of a P-TEFb inhibitor and one or more of a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor to a cancer cell induces apoptosis in the cancer cell. In one embodiment, a combination therapy including one or more of a P-TEFb inhibitor and one or more of a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor increases the potency of any one of the one or more P-TEFb inhibitor and/or one or more of the CBP inhibitor, the p300 inhibitor and/or the CBP/p300 inhibitor when compared to the potency of any one of the component compounds alone (e.g., not in a combination therapy). In another embodiment, administration of a combination therapy of one or more of a P-TEFb inhibitor and one or more of a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor provides a therapeutic synergy between the one or more P-TEFb inhibitor and one or more of the CBP inhibitor, the p300 inhibitor and/or the CBP/p300 inhibitor which enhances the therapeutic potential of the combination relative to one or more of the compounds in isolation. In some embodiments, the combination therapy of one or more of a P-TEFb inhibitor and one or more of a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor exhibits therapeutic synergy between the one or more P-TEFb inhibitor and one or more of the CBP inhibitor, the p300 inhibitor and/or the CBP/p300 inhibitor for blocking adaptive kinome reorganization.

[100] A combination therapy of one or more of a P-TEFb inhibitor and one or more of a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor, in one embodiment, comprises one or more of a BET bromodomain inhibitor and one or more of a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor. Further, the one or more BET bromodomain inhibitor can be a BRD4 inhibitor selected from the group consisting of apabetalone, BI2536, bromosporine, CPI-203, I-BET151, 1-BET762, JQ1, MS436, OTX015, PF-431396, PFI-1, TG-101209, and TG-101348, or combinations thereof. A CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor, is not limited to, but is selected from the group consisting of SGC-CBP30, C646, C375, C146, epigallocatechol gallate (EGCG), garcinol, L002, LTK-14 and PU141, or combinations thereof.

[101] In another embodiment, the present disclosure provides a combination therapy, wherein a single active or a single molecule has the properties of a P-TEFb inhibitor and a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor.

[102] A combination therapy, in some embodiments, comprises one or more of a kinase inhibitor and one or more of a P-TEFb inhibitor with a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor.

[103] In one embodiment, a combination therapy as described herein employs one or more of a lipid kinase inhibitor, a mitogen- activated protein kinase (MAPK) inhibitor, a non-receptor tyrosine kinase inhibitor, a receptor tyrosine kinase (RTK) inhibitor, or a serine/threonine kinase inhibitor, or combinations thereof, as a kinase inhibitor component. In some embodiments, the one or more kinase inhibitor used for the combination therapy presently disclosed is a lipid kinase inhibitor. Lipid kinase inhibitors play a major role in important cellular signaling pathways such as the PI3K/AKT/MTOR pathway. The PI3 K/AKT/MTOR pathway is understood to have an important contribution to healthy cell apoptosis and when overactive, as seen in some cancer cells, cell proliferation is induced due to lack of normal cell apoptosis control. Therefore, in some embodiments, a lipid kinase inhibitor is an appropriate kinase inhibitor for the treatment of disease such as cancer. In one embodiment, a lipid kinase inhibitor is selected from the group consisting of phosphoinositide 3-kinase (PI3K) inhibitor, phosphoinositide 4-kinase (PI4K) inhibitor, and Vps34 inhibitor, or combinations thereof.

[104] In one embodiment, a combination therapy employs one or more of a MAPK inhibitor as the one or more kinase inhibitor. MAPK is involved in the MAPK cascade signaling pathway where a chain of cellular proteins communicate, which results in modified expression in the DNA of cells, causing changes in cellular process such as, e.g., cell division. Dysregulation of the MAPK cascade has been linked to uncontrolled cell proliferation. Accordingly, in one embodiment, one or more of a MAPK inhibitor is an appropriate kinase inhibitor for the treatment of diseases such as cancer. In some embodiments, the one or more MAPK inhibitor is selected from the group consisting of an ARAF inhibitor, a BRAF inhibitor, a CRAF inhibitor, and a MEK inhibitor, or combinations thereof. In a further embodiment, a BRAF inhibitor is selected from a group consisting of ARQ736, AZ628, AZD8055, BEZ235, cetuximab, dabrafenib, dacarbazine, erlotinib, everolimus, GDC-0879, GDC-0941, gefitinib, GSK2118436, imatinib, LGX818, PLX-4720, RAF265, R05212054, SAR245409, SAR2455408, sorafenib, temsirolimus, tomozolomide, vemurafenib, and XL281, or combinations thereof.

[105] In some embodiments, a combination therapy employs one or more of a MEK inhibitor as the one or more kinase inhibitor. In one embodiment, the one or more MEK inhibitor is selected from the group consisting of ARRY438162, AZD6244, binimetinib, CI- 1040, GDC0941, GDC0973, MEK162, PD035901, PD318088, PD334581, PD98059, pimasertib, R05126766, RDEA119, RDEA436, selumetinib, TAK733, trametinib, and XL518, or combinations thereof. Trametinib is an allosteric kinase inhibitor specific for MEK1/2.

[106] In one embodiment, a combination therapy employs one or more of a non-receptor tyrosine kinase inhibitor as the one or more kinase inhibitor. Non-receptor tyrosine kinase are understood to have a major role in the immune system as it regulates, e.g., cell growth, cell proliferation, cell differentiation, cell adhesion, cell migration and ell apoptosis. Thus, in one embodiment, a non-receptor kinase may be selected as an appropriate kinase inhibitor in treating a disease such as, e.g., cancer. In some embodiments, the one or more non-receptor tyrosine kinase inhibitor is selected from the group consisting of Abl inhibitor, a BTK inhibitor, a Jak inhibitor, and a Src inhibitor, or combinations thereof. In a further embodiment, the nonreceptor tyrosine kinase inhibitor is selected from a group consisting of bosutinib, dasatinib, ibrutinib, imatinib, KX2-391, LFM-A13, nilotinib, pacritinib, PF-573228, ponatinib, ruxolitinib, saracatinib, and tofacitinib, or combinations thereof.

[107] In one embodiment, a combination therapy employs one or more of a RTK inhibitor as the one or more kinase inhibitor. RTKs are heavily involved in regulating normal cellular processes as well as play a critical role in the development and progression of many types of cancer. RTKs activate different cellular processes including the MAPK cascade pathways and the PI3K/AKT/MTOR (AKT = protein Kinase B, MTOR = mechanistic target of rapamycin) pathway described herein. Therefore, in one embodiment, a RTK inhibitor is an appropriate kinase inhibitor in the treatment of disease characterized by cell proliferation, such as cancer. In some embodiments, the one or more RTK inhibitor is selected from the group consisting of anaplastic lymphoma kinase (ALK) inhibitor, a c-MET inhibitor, an EGFR inhibitor, an ERBB inhibitor, a FGF inhibitor, a PDGF inhibitor and a VEGF inhibitor, or combinations thereof. In a further embodiment, the RTK inhibitor is selected from a group consisting of afatinib, alectinib (CH5424802)*, AP26113 (Ariad)*, ASP3026 (Astellas US 8,318,702), axitinib, cabozantinib, cediranib, CEP-37440 (Teva)*, ceritinib (LDK378)*, cetuximab, EBI215 (Eternity), entrectinib (RXDX101, Nervano US 8,299,057), erlotinib, foretinib, gefitinib, gilteritinib (ASP2215 US 8,969,336), grandinin, lapatinib, neratinib, panitumumab, pazopanib, pazopanib, PF-06463922 (Pfizer)*, quizartinib, regorafenib, semaxanib, sorafenib, sunitinib, tivantinib, tivoaznib, toceranib, trastuzumab, TSR-011 (Tesaro), vandetanib, and X-396 (Xcovery), or combinations thereof. Commercially available from MedChem Express (Monmouth Junction, NJ, USA).

[108] In one embodiment, a combination therapy employs one or more of a serine/threonine kinase inhibitor as the one or more kinase inhibitor. Serine/threonine kinase are also known to play a major role in regulating cell proliferation, programmed cell death (apoptosis), and cell differentiation. Thus, in one embodiment, one or more of a serine/threonine kinase inhibitor is an appropriate kinase inhibitor for the treatment of a disease, such as cancer. In some embodiments, the one or more serine/threonine kinase inhibitor is selected from a group consisting of enzastaurin, H-7, LY294002, sorafenib, and staurosporine, or combinations thereof.

[109] In one embodiment, a combination therapy employs one or more of a chemotherapeutic compound. A combination therapy, in some embodiments, comprises one or more of a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor and one or more of a chemotherapeutic compound. In one embodiment, the one or more chemotherapeutic compound is a nucleotide analog or precursor analog thereof. In one embodiment, the one or more chemotherapeutic compound which is a nucleotide analog or precursor analog thereof is selected from the group consisting of gemcitabine, azacitidine, azathioprine, capecitabine, cytarabine, doxifluridine, fluorouracil, hydroxyurea, mercaptopurine, methotrexate, and tioguanine. In one embodiment, the chemotherapeutic compound can be gemcitabine. [110] A combination therapy of one or more of a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor and one or more of a chemotherapeutic compound, in some embodiments, results in the inhibition of cancer cell growth. In another embodiment, administering a combination therapy including one or more of a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor and one or more of a chemotherapeutic compound to a cancer cell induces apoptosis in the cancer cell. In one embodiment, a combination therapy including one or more of a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor and one or more of a chemotherapeutic compound increases the potency of any one or more of the CBP inhibitor, the p300 inhibitor and/or the CBP/p300 inhibitor or the one or more chemotherapeutic compound when compared to the potency of any one of the component compounds alone (e.g., not in a combination therapy). In another embodiment, administration of the combination therapy of one or more of a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor and one or more of a chemotherapeutic compound provides a therapeutic synergy between one or more of the CBP inhibitor, the p300 inhibitor and/or the CBP/p300 inhibitor and the one or more chemotherapeutic compound which enhances the therapeutic potential of the combination relative to one or more of the compounds in isolation. In some embodiments, the combination therapy of one or more of a CBP inhibitor, a p300 inhibitor and/or a CBP/p300 inhibitor and one or more of a chemotherapeutic compound exhibits therapeutic synergy between one or more of the CBP inhibitor, the p300 inhibitor and/or the CBP/p300 inhibitor and the one or more chemotherapeutic compound for blocking adaptive kinome reorganization.

[Ill] In some embodiments, the disclosure provides a method of treatment using a combination therapy. In one embodiment, the condition is a cancer driven by dysregulation of a kinase signaling network or a RAS oncogene. In some embodiments, the method of treating a subject with a cancer driven by dysregulation of a kinase signaling network or a RAS oncogene comprises (i) administering to the subject one or more of a compound that inhibits the activity of a kinase and (ii) administering to the subject one or more of a compound that inhibits the activity of P-TEFb or one or more of a compound that inhibits the activity of CBP and/or p300. In one embodiment, the one or more compound that inhibits the activity of a kinase and one or more of the compound that inhibits the activity of P-TEFb and/or the compound that inhibits the activity of CBP and/or p300 are administered simultaneously. In another embodiment, the one or more compound that inhibits the activity of a kinase and one or more of the compound that inhibits the activity of P-TEFb and/or the compound that inhibits the activity of CBP and/or p300 are administered sequentially.

[112] In one embodiment, the method of treating a subject with a cancer driven by dysregulation of a kinase signaling network or a RAS oncogene comprises (i) administering to the subject one or more of a compound that inhibits the activity of positive transcription elongation factor b (P-TEFb) and (ii) administering to the subject one or more of a compound that inhibits the activity of CBP and/or p300. In one embodiment, the one or more compound that inhibits the activity of P-TEFb and the one or more compound that inhibits the activity of CBP and/or p300 are administered simultaneously. In another embodiment, the one or more compound that inhibits the activity of P-TEFb and the one or more compound that inhibits the activity of CBP and/or p300 are administered sequentially.

[113] In one embodiment, the method of treating a subject with a cancer driven by dysregulation of a kinase signaling network or a RAS oncogene comprises (i) administering to the subject one or more of a compound that inhibits the activity of CBP and/or p300 and (ii) administering to the subject one or more of a chemo therapeutic agent. In one embodiment, the chemotherapeutic agent is a nucleotide analog or a precursor analog thereof. In one embodiment, the one or more compound that inhibits the activity of CBP and/or p300 and the one or more chemotherapeutic compound are administered simultaneously. In another embodiment, the one or more compound that inhibits the activity of CBP and/or p300 and the one or more chemotherapeutic compound are administered sequentially.

[114] In one embodiment, the method of treating a subject with a cancer driven by dysregulation of a kinase signaling network or a RAS oncogene comprises (i) administering to the subject one or more of a compound that inhibits the activity of a kinase, (ii) administering to the subject one or more of a compound that inhibits the activity of positive transcription elongation factor b (P-TEFb) and (iii) administering to the subject one or more of a compound that inhibits the activity of CBP and/or p300. In one embodiment, the one or more compound that inhibits the activity of a kinase, the one or more compound that inhibits the activity of P- TEFb and the one or more compound that inhibits the activity of CBP and/or p300 are administered simultaneously. In another embodiment, the one or more compound that inhibits the activity of a kinase, the one or more compound that inhibits the activity of P-TEFb and the one or more compound that inhibits the activity of CBP and/or p300 are administered sequentially.

[115] In another embodiment, this disclosure provides a method of reducing the proliferation rate of a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene by (i) administering to the cancer cell population one or more of a compound that inhibits the activity of a kinase and (ii) administering to the cancer cell population one or more of a compound that inhibits the activity of P-TEFb and/or one or more of a compound that inhibits the activity of CBP and/or p300.

[116] In one embodiment, this disclosure provides a method of reducing the proliferation rate of a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene by (i) administering to the cancer cell population one or more of a compound that inhibits activity of positive transcription elongation factor b (P-TEFb) and (ii) administering to the cancer cell population one or more of a compound that inhibits the activity of CBP and/or p300.

[117] In one embodiment, this disclosure provides a method of reducing the proliferation rate of a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene by (i) administering to the cancer cell population one or more of a compound that inhibits the activity of CBP and/or p300 and (ii) administering to the cancer cell population one or more of a chemotherapeutic agent, wherein said chemotherapeutic agent is a nucleotide analog or a precursor analog thereof.

[118] In one embodiment, this disclosure provides a method of reducing the proliferation rate of a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene by (i) administering to the cancer cell population one or more of a compound that inhibits the activity of a kinase, (ii) administering to the cancer cell population one or more of a compound that inhibits the activity of positive transcription elongation factor b (P-TEFb) and (iii) administering to the cancer cell population one or more of a compound that inhibits the activity of CBP and/or p300.

[119] In another embodiment, disclosure relates to a method of enhancing the rate of apoptosis in a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene, by (i) administering to the cancer cell population one or more of a compound that inhibits the activity of a kinase and (ii) administering to the cancer cell population one or more of a compound that inhibits the activity of P-TEFb and/or the compound that inhibits the activity of CBP and/or p300.

[120] In one embodiment, disclosure relates to a method of enhancing the rate of apoptosis in a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene, by (i) administering to the cancer cell population one or more of a compound that inhibits activity of positive transcription elongation factor b (P-TEFb) and (ii) administering to the cancer cell population one or more of a compound that inhibits the activity of CBP and/or p300.

[121] In one embodiment, disclosure relates to a method of enhancing the rate of apoptosis in a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene, by (i) administering to the cancer cell population one or more of a compound that inhibits the activity of CBP and/or p300 and (ii) administering to the cancer cell population one or more of a chemotherapeutic agent, wherein said chemotherapeutic agent is a nucleotide analog or a precursor analog thereof.

[122] In one embodiment, disclosure relates to a method of enhancing the rate of apoptosis in a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene, by (i) administering to the cancer cell population one or more of a compound that inhibits the activity of a kinase, (ii) administering to the cancer cell population one or more of a compound that inhibits the activity of positive transcription elongation factor b (P-TEFb) and (iii) administering to the cancer cell population one or more of a compound that inhibits the activity of CBP and/or p300.

[123] In one embodiment, the cancer to be treated with the methods disclosed herein is a blood-borne cancer. In some embodiments, the blood-borne cancer includes but is not limited to AML (acute myeloid leukemia), CML (chronic myeloid leukemia), a hematopoietic system cancer, lymphatic system, and lymphoma.

[124] In one embodiment, the cancer to be treated with the methods disclosed herein is a solid tumor or cancer. In some embodiments, the solid tumor or cancer includes but is not limited to cancer of the bladder, bone, brain, colon, colorectal, ERBB2-positive breast, gastric, gastrointestinal, genitourinary tract, glioma, head and neck, larynx, lymphoma, lung, melanoma, non-small cell lung, ovarian, ovary, pancreatic cancer, prostate, small cell lung, stomach, and triple negative breast. [125] The method of administration of the kinase inhibitor and P-TEFb inhibitor can be any method commonly known in the art of pharmaceutical medicine. Non-limiting examples of administration pathways includes orally, such as in the form of tablets, capsules, granules, syrups, elixirs, or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, intrathecal, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a drug-releasing skin patch, cream or ointment; intravaginally; by drench, transdermally; intradermally; pulmonary; by intra-uterine; by the use of an aerosol; or rectally such as in the form of suppositories; in dosage unit formulations containing nontoxic, pharmaceutically acceptable vehicles or diluents.

[126] In one embodiment, the compounds or the combination of compounds of the present disclosure can be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising the compounds presented in this disclosure, for example, by using polymer coatings using enteric polymers, water-soluble polymers, water-insoluble polymers, gastrosoluble polymers, and combinations thereof.

EXAMPLES

MEK Inhibitors for Triple Negative Breast Cancer Cells

[127] Triple negative breast cancer (TNBC) is heterogeneous with patients exhibiting at least two molecular subtypes, basal-like (BL) and claudin-low (CL). These two distinct subtypes of

TNBC are commonly treated as single disease, although it is understood that BL and CL TNBC have different baseline kinome activation states and responds differently to various kinase inhibitors. This is one of the reasons for the difficulty in treating TNBC with a single kinase inhibitor. The CL phenotype has been shown to have a growth selective advantage over the BL phenotype in a continuous growth test of human SUM229 breast cancer cells treated with 10 nM trametinib. Trametinib is a highly selective MEK inhibitor that binds to the allosteric regulatory site of MEK1/2 resulting in kinase activity inhibition and the loss of ERK1/2 phophorylation and activation.

Example 1: Kinome reprogramming in TNBC patient with trametinib treatment

[128] Ten TNBC patients were enrolled in a seven-day window trail in which each patient was given trametinib daily for seven days. Pre-treatment core biopsies and post-treatment tumors were subtyped as CL or BL using gene arrays and analyzed for kinome reprogramming.

[129] Five patients had the same TNBC subtype in their pre-treatment biopsy and resected tumor (4 BL pre- and BL post- trametinib, 1 CL pre- and CL post-trametinib). Differences in the subtypes between pre- and post-treatment tumors from the other five patients most likely resulted from core biopsy sampling variability. Therefore, the analysis of kinome reprogramming was restricted to pre- and post-treatment tumors having a common BL or CL subtype. The clinical characteristics and kinome reprogramming in those five patients with common BL or CL subtypes are show below in Table 1. All five patients were female, had no prior therapy, and showed MEKl inhibition. The reprogramming response was measured by both immunoblotting and mRNA expression analyses. Patient 2 was analyzed only by mRNA analysis due to sample limitations. The reprogramming response demonstrates the upregulated activities.

Table 1. Reprogramming Response to Trametinib in TNBC Patients Patient TNBC Trametinib

Age Race Reprogramming Response # Subtype Dose

2 67 White CL/CL 1 .5 mg Daily DDR2, CSF1 R, VEGFR2, PDGFRp

3 78 White BL/BL 2 mg Daily IGF1 R, DDR1 , FRK, FGFR2

African

4 51 BL/BL 2 mg Daily DDR1 , IGF1 R, KIT, SRC, FRK, p-AKT

American

African

7 57 BL/BL 2 mg Daily FGFR2, KIT, FRK, p-AKT

American

African Activated Pre- and Post-Treatment

8 41 BL/BL 2 mg Daily

American FGFR2, KIT, DDR1

DDR1 and DDR2 = discoidin domain receptor family, member 1 and member 2, respectively; CSF1R = Colony stimulating factor 1 receptor; VEGFR2 = vascular endothelial growth factor receptor 2; PDGFR = platelet-derived growth factor receptor-beta; IGF1R = insulin-like growth factor 1 receptor; FRK = Fyn-related kinase; KIT = receptor tyrosine kinase protein, in humans, encoded by the KIT gene.

[130] Tumor cells from patients 2, 3, 7, and 8 in the seven day trametinib study showed sustained inhibition of MEK1 but not MEK2 (Fig. 1). Additionally, inhibition of ERK1 was not observed. The lack of MEK2 inhibition inconsistent with kinome reprogramming and this result suggest that BL tumors will escape MEK inhibitors by failure to sustain MEK2 inhibition.

[131] The CL phenotype has been shown to possess a selective advantage in cell growth, CL cell line MDA-MB-231 was used to perform a synthetic enhancement screen using siRNA knockdown of all kinases encoded in the human kinome. The top hits of this screen, which identified a synthetic enhancer of MEK inhibitor-induced growth arrest of CL MDA-MB-231 cells, included BET bromodomain-encoded kinase, BRD4. BET bromodomain inhibitors are known to inhibit transcription of important oncogenic proteins such as c-MYC (a regulator gene that codes for a transcription factor). Kinome reprogramming is known to have transcriptional component, therefore, BRD4 which is a core component of the P-TEFb transcriptional elongation complex was further selected for the study of inhibiting kinome reprogramming.

[132] BRD4 inhibitors JQ1 and I-BET151 were tested alone and in conjunction with MEK inhibitors.

Example 2: Short term co-treatment of SUM159 and SUM229 cells with trametinib and BRD4 inhibitor (48 h)

[133] Human breast cancer cells BL SUM229 and CL SUM159 were treated with trametinib (10 nM) alone or in combination with a BRD4 inhibitor, either JQ1 (300 nM) or I-BET151 (1 μΜ) for 48 hours. The western blot plot showing the results is represented in Figure 2. JQ1 and I-BET151 in combination with trametinib inhibited expression of many kinases including RTKs involved in reprogramming responses to trametinib alone. This supports the hypothesis that JQ1 and I-BET151 act via inhibition of BET bromodomain function involved in BRD4 regulation of transcription.

[134] It was demonstrated that JQ1 strongly suppressed multiple tyrosine kinases involved in MEK inhibitor-mediated kinome reprogramming in human breast cancer cells SUM229 and SUM159 cells. In particular, JQ1 alone repressed transcription of PDGFRa/β (PDGFR = platelet-derived growth factor receptor-alpha/beta), AXL (an enzyme, in humans, encoded by the AXL gene), DDR1 and DDR2 in SUM159 cells. Additionally, JQ1 in combination with tramatenib inhibited the MEK inhibitor-induced protein expression of multiple RTKs in different BL and CL cell lines. Similarly, BRD4 inhibitor I-BET151 inhibited expression of multiple RTKs involved in kinome reprogramming response to MEK inhibitors. These studies were based on treatment of cancer cell lines for approximately 48 hours.

[135] The identification of BRD4 inhibitors as inhibitors of kinome reprogramming was successful as described. As mentioned previously, the rationale in identifying inhibitors of kinase reprogramming to obtain prolonged therapeutic use of kinase inhibitors. Accordingly, the durability and robustness of the combination therapy of a kinase inhibitor and a BRD4 inhibitor which was identified was then evaluated.

Example 3: Longer term co-treatment of SUM159 and SUM229 cells with trametinib and BRD4 inhibitor (4 weeks)

[136] Human breast cancer cells BL SUM229, CL SUM159, CL MDA-MB-231, and BL HCC1806 were treated with trametinib (1-100 nM) alone or in combination with a BRD4 inhibitor JQ1 (200-300 nM). The quantification of crystal violet staining plot is shown in Figure 3 (*p value < 0.05). The results demonstrate that the combination of trametinib and JQ1 strongly inhibited the growth of the CL SUM159, CL MDA-MB-231, and BL SUM229 cells. Trametinib or JQ1 alone was unable to maintain a durable growth inhibition and resistance was developed over the duration of the test.

[137] Figure 3 also demonstrate that BL HCC1806 weakly escaped the combination treatment, which may suggest that some TNBC tumors will develop resistance to the combination therapy.

[138] The BET bromodomain protein BRD4 and members of the P-TEFb complex (Fig. 4) were found to be required for adaptive kinome reprogramming in response to RTK inhibitors and kinase inhibitors targeting MEK, PI3K and AKT in different breast and pancreatic cancer models. The RNAi knockdown of CDK9, but not knockdown of CDK7 or CDK8, inhibited adaptive reprogramming of SUM149PT cells in response to MEK inhibition by trametinib (Fig. 5A). Similarly, knockdown of CDK9 inhibited adaptive reprogramming in response to trametinib in the claudin-low SUM159PT cells (Fig. 5B). Studies with a commercially available CDK9 "tool compound" inhibitor (HY 16462), also blocked adaptive kinome reprogramming (Fig. 6). [139] Inhibition of CDK9 with a chemical precursor to NVP2 (HY 16462) prevents trametinib-induced kinome reprogramming in TNBC cells. Knockdown of CDK9 confirmed the role of this kinase in the adaptive response (Figs. 5, 6). These results are consistent with a highly selective and potent inhibition of CDK9 in vitro (Fig. 7).

RNA Pol II Ser2 phosphorylation

[140] The C-Terminal Domain (CTD) is a direct substrate for CDK9 phosphorylation. CDK9 phosphorylates Ser 2 of the CTD (P-Ser2), an event required for RNA Pol II dependent transcription elongation. We have shown that inhibition of P-Ser2 correlates with inhibition of kinome reprogramming (data not shown).

MCLl as Cell-Based Indicator of CDK9 Inhibition

[141] MCLl is an anti-apoptotic protein dependent on CDK9 activity for continuous transcriptional elongation (Fig. 8). Inhibition of CDK9 results in a rapid loss of MCLl from cells and an increase in cell death.

[142] It was demonstrated that JQ1 alone or trametinib alone could not sustain a durable growth inhibition of BL and CL TNBC cells, as resistance was developed for both inhibitors over the 30 day treatment trial. In contrast, the combination of JQ1 and trametinib was successful in inhibiting cell growth for the CL SUM159, CL MDA-MB-231, and SUM229 cells over the 30 days. The result demonstrated that JQl/trametinib combination therapy effectively blocked the reprogramming and reactivation of MEK-ERK pathways.

Receptor Tyrosine Kinase Inhibitors for Triple Negative Breast Cancer Cells

[143] Similar to the MEK inhibitor study described above, the inventors studied tyrosine kinase inhibitor, lapatinib, which inhibits human epidermal growth factor receptor 2 (ERBB2). ERBB2 belongs to the family of RTKs. It has been demonstrated that ERBB2 oncogene is amplified or overexpressed in roughly 25% of breast cancers and is understood as the primary driver of tumor cell growth. ERBB2-targeted single kinase therapy also suffers from resistance development. One major mechanism of lapatinib resistance is believed to be due to transcriptional and post-transcriptional upregulation of ERBB3 (human epidermal growth factor receptor 3). The adaptive kinome reprogramming due to lapatinib was determined using MIB/MS as described herein. The activation of multiple RTKs, SRC family kinases, FAK, and members of other intracellular networks downstream of RTKs, was observed.

[144] When lapatinib was combined with JQ1 in the treatment of SLBR-3 and BT474 luminal ERBB2+ breast cancer cells, it showed strong growth arrest or resulted in regression of cell numbers as a result of 48 hour treatment, whereas lapatinib alone was less successful. Additionally the combination of JQl/lapatinib was demonstrated to be effective in an assay carried out over four week period. Also, similar results were obtained with I-BET762/lapatinib and I-BET151/lapatinib combinations.

Example 4: Cell Viability Assay

[145] SUM159 human triple negative breast cancer cells, either wild type (wt) or Trametinib resistant (R) are seeded in 96 well plates at a density of 200 - 400 cells per well (wt) or 400 - 1000 cells per well (R). SKBR3 human HER2-positive breast cancer cells are seeded at a density of 4000 cells/well, PANC1 human pancreatic carcinoma cells are seeded at a density of 1500 cells/well, and H358 human non-small cell lung cancer cells are seeded at a density of 2000 cells/well. Cells are grown overnight in a 37 degree humidified incubator. The following day, growth media is removed and replaced with media containing the indicated concentrations of drug 'A' (e.g. Trametinib, Lapatinib, or Gemcitabine) either with or without a fixed concentration (usually approximately an IC40 - IC₆o concentration of drug 'B' (e.g. SGC-CBP 30, (+)JQ1 or DMSO). The cells are then incubated in a 37 degree incubator for 72 hours or the indicated number of days. The growth media and drugs are replaced every 24 hours. All wells have a final concentration of 0.06 % DMSO (All stock drugs are dissolved in 100% DMSO). Following the drug treatment, assays are performed using The CellTiter-Glo Luminescent Cell Viability Assay (Promega #G7572). The assay measures the amount of ATP present which correlates with the number of viable cells present in each well. Luminescence is measured on a PHERAstar plate reader.

[146] One positive result in the cell viability assay is defined as a shift to the left in the dose response curve of drug 'A' in the presence of a fixed concentration of drug 'B' compared to a control curve in the absence of drug 'B,' thus indicating an increase in the potency of drug 'A' when combined with drug 'B' (e.g., FIG 12). Another positive result is defined as a larger decrease in cell viability when drugs 'A' and 'B' are used in combination compared to use as a single agent (e.g., Fig. 16, PANC1, or Fig. 17, SKBR3).

[147] The SUM159wt cell viability assay dose response result for 72 hour drug treatment with MEK inhibitor Trametinib (drug Ά') and ±100 nM BET bromodomain inhibitor (+)JQ1 (drug 'B') is shown in Figure 9. The combination of Trametinib and (+)JQ1 show synergy in growth inhibition as the control (Trametinib only) IC50 of 3.6 nM was shifted to an IC50 of 0.61 nM with (+)JQl.

[148] The SUM159R cell viability assay dose response result for 72 hour drug treatment with MEK inhibitor Trametinib (drug Ά') and ±100 nM BET bromodomain inhibitor (+)JQ1 (drug 'B') is shown in Figure 10. Trametinib is less potent in SUM159R cells (IC50 = 83 nM) compared to SUM159wt cells (IC50 = 3.6 nM, Fig. 9). The combination of Trametinib and (+)JQ1 show synergy in growth inhibition as the control (Trametinib only) IC50 of 83 nM was shifted to an IC50 of 13 nM with (+)JQ1, thus partially restoring Trametinib potency in SUM159R cells..

[149] The SUM159R cell viability assay dose response result for 7 day drug treatment with MEK inhibitor Trametinib (drug Ά') and ±100 nM BET bromodomain inhibitor (+)JQ1 (drug 'B ') is shown in Figure 11. The combination of Trametinib and (+)JQ1 show synergy in growth inhibition as the control (Trametinib only) IC50 of 45 nM was shifted to an IC50 of 7.6 nM with

(+)JQi

[150] The SUM159wt cell viability assay dose response result for 72 hour drug treatment with MEK inhibitor Trametinib (drug Ά') and ±10 μΜ CBP/p300 inhibitor SGC-CBP30 (drug 'B') is shown in Figure 12. The combination of Trametinib and SGC-CBP30 show synergy in growth inhibition as the control (Trametinib only) IC50 of 1.6 nM was shifted to an IC50 of 0.08 nM with SGC-CBP30. As a model for normal breast epithelium, a comparable assay in the human mammary epithelial cell line, HuMEC, displays no change in the IC50 of Trametinib assayed in the presence or absence of SGC-CBP30 (data not shown).

[151] The SUM159wt cell viability assay dose response result for 72 hour drug treatment with CBP/p300 inhibitor SGC-CBP30 (drug Ά') and ±100 nM BET bromodomain inhibitor (+)JQ1 (drug 'Β') is shown in Figure 13. The combination of (+)JQ1 and SGC-CBP30 show synergy in growth inhibition as IC50 of 11 μΜ in the control (SGC-CBP30 only) was shifted to IC50 of 2.2 μΜ with (+)JQ1.

[152] The SUM159wt cell viability assay dose response result for 72 hour drug treatment with BET bromodomain inhibitor (+)JQ1 (drug Ά') and ±10 μΜ CBP/p300 inhibitor SGC- CBP30 (drug 'Β') is shown in Figure 14. The combination of (+)JQ1 and SGC-CBP30 show synergy in growth inhibition as IC50 of 73 nM in the control ((+)JQ1 only) was shifted to IC50 of 15 nM with SGC-CBP30.

[153] The H385 non-small cell lung cancer cell viability assay dose response result for 72 hour drug treatment with MEK inhibitor Trametinib (drug Ά') and ±10 μΜ CBP/p300 inhibitor SGC-CBP30 (drug 'B') is shown in Figure 15. The combination of Trametinib and SGC-CBP30 show synergy in growth inhibition as IC50 of 24 nM in the control (Trametinib only) was shifted to IC50 of 4 nM with SGC-CBP30. [154] The result for PANC1 human pancreatic carcinoma cell viability assay time course of drug treatment with the chemotherapeutic compound, 3 μΜ Gemcitabine (drug Ά'), or 10 μΜ CBP/p300 inhibitor SGC-CBP30 (drug 'B'), or the two drug combination is shown in Figure 16. Six day treatment with the combination of Gemcitabine and SGC-CBP30 resulted in nearly complete elimination of viable cells.

[155] The result for SKBR3 human HER2-positive breast cancer cell viability assay time course of drug treatment with the EGFR and ErbB2 inhibitor 30 nM Lapatinib (drug Ά') or 10 μΜ CBP/p300 inhibitor SGC-CBP30 (drug 'Β'), or the two drug combination is shown in Figure 17. Six day treatment with the combination of Lapatinib and SGC-CBP30 resulted in a greater decrease in viable cells than either drug alone.

[156] It should be understood that the above description is only representative of illustrative embodiments and examples. For the convenience of the reader, the above description has focused on a limited number of representative examples of all possible embodiments, examples that teach the principles of the disclosure. The description has not attempted to exhaustively enumerate all possible variations or even combinations of those variations described. That alternate embodiments may not have been presented for a specific portion of the disclosure, or that further undescribed alternate embodiments may be available for a portion, is not to be considered a disclaimer of those alternate embodiments. One of ordinary skill will appreciate that many of those undescribed embodiments, involve differences in technology and materials rather than differences in the application of the principles of the disclosure. Accordingly, the disclosure is not intended to be limited to less than the scope set forth in the following claims and equivalents.

INCORPORATION BY REFERENCE

[157] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.

Claims

CLAIMS What is claimed is:

1. A method for inhibiting growth of a cancer cell which comprises administering to the cancer cell a kinase inhibitor and a positive transcription elongation factor b (P-TEFb) inhibitor, a CBP inhibitor, a p300 inhibitor, or a CBP/p300 inhibitor, wherein the P- TEFb inhibitor, a CBP inhibitor, a p300 inhibitor, or a CBP/p300 inhibitor is administered in an effective amount to prevent kinome reorganization and substantial resistance of the cancer cell to the kinase inhibitor.

2. A method for inducing apoptosis in a cancer cell comprising administering to the cancer cell a kinase inhibitor and a positive transcription elongation factor b (P-TEFb) inhibitor.

3. A method for inducing apoptosis in a cancer cell comprising administering to the cancer cell a kinase inhibitor and a CBP inhibitor, a p300 inhibitor, or a CBP/p300 inhibitor.

4. The method of claim 1 or 2, wherein administering to the cancer cell comprises contacting the cancer cell with a kinase inhibitor and a positive transcription elongation factor b (P-TEFb) inhibitor.

5. The method of claim 1 or 3, wherein the administering to the cancer cell comprises contacting the cancer cell with a kinase inhibitor and a CBP inhibitor, a p300 inhibitor, or a CBP/p300 inhibitor.

6. The method of claim 1 or 2, wherein the P-TEFb inhibitor is a BRD4 inhibitor.

7. The method of claim 6, wherein the P-TEFb inhibitor is a specific BRD4 inhibitor.

8. The method of claim 7, wherein the specific BRD4 inhibitor is apabetalone, BI2536, bromosporine, CPI-203, I-BET151, I-BET762, JQ1, MS436, OTX015, PF-431396, PFI-1, TG-101209, or TG-101348, or combinations thereof.

9. The method of claim 1 or 2, wherein the P-TEFb inhibitor is a CDK9 inhibitor.

10. The method of claim 9, wherein the P-TEFb inhibitor is a specific CDK9 inhibitor.

11. The method of claim 10, wherein the specific CDK9 inhibitor is AT7519, AZD5438, CYC065, CYC202, dinaciclib, EXEL3700, EXEL8647, flavopiridol, HMR1275, HY- 15878, HY-16462, LDC000067, MK7965, NVP1, NVP2, ON108600, P276-00, PHA- 767491, PTEFb-BAYl, Roscovitine, SEL120, or SNS032, or combinations thereof.

12. The method of claim 1 or 2, wherein the kinase inhibitor is a lipid kinase inhibitor, a mitogen-activated protein kinase (MAPK) inhibitor, non-receptor tyrosine kinase inhibitor, a receptor tyrosine kinase (RTK) inhibitor, or a serine/threonine kinase inhibitor, or combinations thereof.

13. The method of claim 5, wherein the administering to the cancer cell comprises contacting the cancer cell with a kinase inhibitor and a CBP inhibitor.

14. The method of claim 5, wherein the administering to the cancer cell comprises contacting the cancer cell with a kinase inhibitor and a p300 inhibitor.

15. The method of claim 5, wherein the administering to the cancer cell comprises contacting the cancer cell with a kinase inhibitor and a CBP/p300 inhibitor, wherein the CBP/p300 inhibitor is a single inhibitor.

16. The method of claim 5, wherein the CBP inhibitor, the p300 inhibitor, or the CBP/p300 inhibitor is SGC-CBP30, C646, C375, C146, epigallocatechol gallate (EGCG), garcinol, L002, LTK-14 or PU141.

17. The method of claim 12, wherein the lipid kinase inhibitor is a phosphoinositide 3- kinase, (PI3K) inhibitor, phosphoinositide 4-kinase (PI4K) inhibitor, or Vps34 inhibitor, or combinations thereof.

18. The method of claim 12, wherein the mitogen-activated protein kinase (MAPK) inhibitor is an ARAF inhibitor, a BRAF inhibitor, a CRAF inhibitor, or a MEK inhibitor, or combinations thereof.

19. The method of claim 18, wherein the BRAF inhibitor is ARQ736, AZ628, AZD8055, BEZ235, cetuximab, dabrafenib, dacarbazine, erlotinib, everolimus, GDC-0879, GDC- 0941, gefitinib, GSK2118436, imatinib, LGX818, PLX-4720, RAF265, RO5212054, SAR245409, SAR2455408, sorafenib, temsirolimus, tomozolomide, vemurafenib, or XL281, or combinations thereof.

20. The method of claim 18, wherein the MEK inhibitor is ARRY438162, AZD6244, binimetinib, CI-1040, GDC0941, GDC0973, MEK162, PD035901, PD318088, PD334581, PD98059, pimasertib, R05126766, RDEA119, RDEA436, selumetinib, TAK733, trametinib, or XL518, or combinations thereof.

21. The method of claim 12, wherein the non-receptor tyrosine kinase inhibitor is an Abl inhibitor, a BTK inhibitor, a Jak inhibitor, or a Src inhibitor, or combinations thereof.

22. The method of claim 12, wherein the non-receptor tyrosine kinase inhibitor is bosutinib, dasatinib, ibrutinib, imatinib, KX2-391, LFM-A13, nilotinib, pacritinib, PF-573228, ponatinib, ruxolitinib, saracatinib, or tofacitinib, or combinations thereof.

23. The method of claim 12, wherein the RTK inhibitor is anaplastic lymphoma kinase (ALK) inhibitor, a c-MET inhibitor, an EGFR inhibitor, an ERBB inhibitor, a FGF inhibitor, a PDGF inhibitor or a VEGF inhibitor, or combinations thereof.

24. The method of claim 12, wherein the RTK inhibitor is afatinib, axitinib, cabozantinib, cediranib, cetuximab, erlotinib, foretinib, gefitinib, grandinin, lapatinib, neratinib, panitumumab, pazopanib, pazopanib, quizartinib, regorafenib, semaxanib, sorafenib, sunitinib, tivantinib, tivoaznib, toceranib, trastuzumab, or vandetanib, or combinations thereof.

25. The method of claim 12, wherein the serine/threonine kinase inhibitor is enzastaurin, H-7, LY294002, sorafenib, or staurosporine, or combinations thereof.

26. A method for inhibiting growth of a cancer cell which comprises administering to the cancer cell a CBP inhibitor, a p300 inhibitor, or a CBP/p300 inhibitor and a P-TEFb inhibitor or a chemotherapeutic compound;

wherein said chemotherapeutic compound is a nucleotide analog or a precursor analog thereof; and

wherein the CBP inhibitor, the p300 inhibitor, or the CBP/p300 inhibitor and the P- TEFb inhibitor or the chemotherapeutic compound are administered in an effective amount to prevent kinome reorganization.

27. A method for inducing apoptosis in a cancer cell comprising administering to the cancer cell a CBP inhibitor, a p300 inhibitor, or a CBP/p300 inhibitor and a P-TEFb inhibitor.

28. A method for inducing apoptosis in a cancer cell comprising administering to the cancer cell a CBP inhibitor, a p300 inhibitor, or a CBP/p300 inhibitor and a chemotherapeutic compound, wherein said chemotherapeutic compound is a nucleotide analog or a precursor analog thereof.

29. The method of claim 26 or 27, wherein the administering to the cancer cell comprises contacting the cancer cell with a CBP inhibitor, a p300 inhibitor, or a CBP/p300 inhibitor and a P-TEFb inhibitor.

30. The method of claim 29, wherein the P-TEFb inhibitor is a BRD4 inhibitor selected from the group consisting of apabetalone, BI2536, bromosporine, CPI-203, 1-BET151, I-BET762, JQ1, MS436, OTX015, PF-431396, PFI-1, TG-101209, TG-101348, and combinations thereof.

31. The method of claim 29, wherein the CBP/p300 inhibitor is SGC-CBP30, C646, C375, C146, epigallocatechol gallate (EGCG), I-CBP112, ISOX-DUAL, garcinol, L002, LTK-14, PF-CBP1 or PU141.

32. The method of claim 26 or 28, wherein the administering to the cancer cell comprises contacting the cancer cell with the CBP inhibitor, the p300 inhibitor, and/or the CBP/p300 inhibitor and the chemotherapeutic compound.

33. The method of claim 32, wherein the chemotherapeutic compound is selected from the group consisting of azacitidine, azathioprine, capecitabine, cytarabine, doxifluridine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, and tioguanine.

34. The method of claim 33, wherein the chemotherapeutic compound is gemcitabine.

35. A method for inhibiting growth of a cancer cell which comprises administering to the cancer cell a CBP inhibitor, a p300 inhibitor, or a CBP/p300 inhibitor and a P-TEFb inhibitor and a kinase inhibitor wherein the CBP inhibitor, the p300 inhibitor, or the CBP/p300 inhibitor and the P-TEFb inhibitor and the kinase inhibitor is administered in an effective amount to prevent kinome reorganization.

36. A method for inducing apoptosis in a cancer cell comprising administering to the cancer cell a CBP inhibitor, a p300 inhibitor, or a CBP/p300 inhibitor and a P-TEFb inhibitor and a kinase inhibitor.

37. The method of claim 35 or 36, wherein the administering to the cancer cell comprises contacting the cancer cell with a CBP inhibitor, a p300 inhibitor, or a CBP/p300 inhibitor and a P-TEFb inhibitor and a kinase inhibitor.

38. A method of treating a subject with a cancer driven by dysregulation of a kinase signaling network or a RAS oncogene, the method comprising (i) administering to the subject a compound that inhibits the activity of a kinase and (ii) administering a compound that inhibits the activity of positive transcription elongation factor b (P- TEFb) or a compound that inhibits the activity of CBP and/or p300.

39. The method of claim 38, wherein the compound that inhibits the activity of a kinase and the compound that inhibits the activity of positive transcription elongation factor b (P-TEFb) or the compound that inhibits the activity of CBP and/or p300 are administered simultaneously.

40. The method of claim 38, wherein the compound that inhibits the activity of a kinase and the compound that inhibits the activity of positive transcription elongation factor b (P-TEFb) or the compound that inhibits the activity of CBP and/or p300 are administered sequentially.

41. A method of treating a subject with a cancer driven by dysregulation of a kinase signaling network or a RAS oncogene, the method comprising (i) administering to the subject a compound that inhibits the activity of positive transcription elongation factor b (P-TEFb) and (ii) administering a compound that inhibits the activity of CBP and/or p300.

42. The method of claim 41, wherein the compound that inhibits positive transcription elongation factor b (P-TEFb) and the compound that inhibits the activity of CBP and/or p300 are administered simultaneously.

43. The method of claim 41, wherein the compound that inhibits positive transcription elongation factor b (P-TEFb) and the compound that inhibits the activity of CBP and/or p300 are administered sequentially.

44. A method of treating a subject with a cancer driven by dysregulation of a kinase signaling network or a RAS oncogene, the method comprising (i) administering to the subject a compound that inhibits the activity of CBP and/or p300 and (ii) administering a chemotherapeutic compound, wherein said chemotherapeutic compound is a nucleotide analog or a precursor analog thereof.

45. The method of claim 44, wherein the compound that inhibits the activity of CBP and/or p300 and the chemotherapeutic compound are administered simultaneously.

46. The method of claim 44, wherein the compound that inhibits the activity of CBP and/or p300 and the chemotherapeutic compound are administered sequentially.

47. A method of treating a subject with a cancer driven by dysregulation of a kinase signaling network or a RAS oncogene, the method comprising (i) administering to the subject a compound that inhibits the activity of a kinase, (ii) administering to the subject a compound that inhibits the activity of positive transcription elongation factor b (P- TEFb) and (iii) administering a compound that inhibits the activity of CBP and/or p300.

48. The method of claim 47, wherein the compound that inhibits the activity of a kinase, the compound that inhibits positive transcription elongation factor b (P-TEFb) and the compound that inhibits the activity of CBP and/or p300 are administered simultaneously.

49. The method of claim 47, wherein the compound that inhibits the activity of a kinase, the compound that inhibits positive transcription elongation factor b (P-TEFb) and the compound that inhibits the activity of CBP and/or p300 are administered sequentially, in any order.

50. A method of reducing the proliferation rate of a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene, the method comprising (i) administering to the cancer cell population a compound that inhibits the activity of a kinase and (ii) administering to the cancer cell population a compound that inhibits the activity of positive transcription elongation factor b (P- TEFb) or the compound that inhibits the activity of CBP and/or p300.

51. A method of enhancing the rate of apoptosis in a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene, the method comprising (i) administering to the cancer cell population a compound that inhibits the activity of a kinase and (ii) administering to the cancer cell population a compound that inhibits the activity of positive transcription elongation factor b (P- TEFb) or the compound that inhibits the activity of CBP and/or p300.

52. A method of reducing the proliferation rate of a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene, the method comprising (i) administering to the cancer cell population a compound that inhibits activity of positive transcription elongation factor b (P-TEFb) and (ii) administering to the cancer cell population a compound that inhibits the activity of CBP and/or p300.

53. A method of enhancing the rate of apoptosis in a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene, the method comprising (i) administering to the cancer cell population a compound that inhibits activity of positive transcription elongation factor b (P-TEFb) and (ii) administering to the cancer cell population a compound that inhibits the activity of CBP and/or p300.

54. A method of reducing the proliferation rate of a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene, the method comprising (i) administering to the cancer cell population a compound that inhibits the activity of CBP and/or p300 and (ii) administering to the cancer cell population a chemotherapeutic compound, wherein said chemotherapeutic compound is a nucleotide analog or a precursor analog thereof.

55. A method of enhancing the rate of apoptosis in a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene, the method comprising (i) administering to the cancer cell population a compound that inhibits the activity of CBP and/or p300 and (ii) administering to the cancer cell population a chemotherapeutic compound, wherein said chemotherapeutic compound is a nucleotide analog or a precursor analog thereof.

56. A method of reducing the proliferation rate of a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene, the method comprising (i) administering to the cancer cell population a compound that inhibits the activity of a kinase, (ii) administering to the cancer cell population a compound that inhibits the activity of positive transcription elongation factor b (P- TEFb) and (iii) administering a compound that inhibits the activity of CBP and/or p300.

57. A method of enhancing the rate of apoptosis in a cancer cell population, wherein the cancer is driven by dysregulation of a kinase signaling network or a RAS oncogene, the method comprising (i) administering to the cancer cell population a compound that inhibits the activity of a kinase, (ii) administering to the cancer cell population a compound that inhibits the activity of positive transcription elongation factor b (P- TEFb) and (iii) administering a compound that inhibits the activity of CBP and/or p300.

58. The method of any one of claims 1-37 or 50-57, wherein the cancer cell is a blood- borne cancer cell.

59. The method of claim 58, wherein the blood-borne cancer cell is AML, CML, a

hematopoietic system cancer, lymphatic system, or lymphoma cell.

60. The method of any one of claims 1-37 or 50-57, wherein the cancer is a solid cancer cell.

61. The method of claim 60, wherein the solid cancer is bladder, bone, brain, colon,

colorectal, ERBB2-positive breast, gastric, gastrointestinal, genitourinary tract, glioma, head and neck, larynx, lymphoma, lung, melanoma, non-small cell lung, ovarian, ovary, pancreatic cancer, prostate, small cell lung, stomach, or triple negative breast cancer cell.