KR20160080418A - Method for providing the information for predicting the cancer treatment effect of Pan-ErbB inhibitors - Google Patents

Abstract

The present invention relates to a method for providing information related to the prediction of a cancer treatment effect of a pan-ErbB inhibitor by confirming an activity of protein reversionless 3-like (REV3L) from a biological sample of a cancer patient. The method according to the present invention can administrate a pan-ErbB inhibitor into selected patients who can show a high treatment effect with respect to the pan-ErbB inhibitor, so a patient-customized treatment is possible and a treatment effect with respect to the pan-ErbB inhibitor can be improved. Moreover, an administration pharmaceutical composition including an REV3L inhibitor and a pan-ErbB inhibitor as active ingredients and utilized in treating cancer is expected to improve an effect in treating patients having resistance against a pan-ErbB inhibitor.

Description

[0001] The present invention relates to a method for providing information on the prediction of cancer treatment effect of PAN-ErbB inhibitor,

The present invention relates to a method for providing information on the prediction of cancer treatment effect of Pan-ErbB inhibitor by confirming the activity of REV3L.

The ErbB family (ErbB-1, ErbB-2, ErbB-3, and ErbB-4), a transmembrane receptor tyrosine kinase, plays an important role in the development and maintenance of various tumors , Various attempts have been made to use ErbB inhibitors as cancer treatments (Cancer Cell (2014) 25: 282-303). As a result of these attempts, various Pan-ErbB inhibitors such as dacomitinib, canertinib, and afatinib have been developed and clinical trials have been actively conducted. However, treatments with Pan-ErbB inhibitors showed excellent anticancer effects in early patients only in some patients with mutations in the ErbB family, and most other patients showed resistance to these inhibitors, . It is also known that DakoMitinib does not improve overall survival compared to existing drugs at the clinical testing stage. Therefore, in order to effectively treat cancer by using Pan-ErbB inhibitor, there is a need for a combination therapy of drugs and a customized treatment method for predicting the therapeutic effect on the drug. However, studies on the mutation of the ErbB family against Pan-ErbB inhibitor resistance have been actively carried out, but there is no study on the linkage with other genes.

On the other hand, head and neck cancer refers to a tumor that occurs on the face and neck except the brain. It is a cancer that occurs in tissues such as nasal cavity, pharynx, pharynx, salivary gland, thyroid gland, It accounts for about 5% of tumors. In addition, the incidence of head and neck cancer is gradually increasing with the progress of population aging around the world. The most common treatment methods for head and neck cancer are radio-theraphy, resection by surgery, and chemotherapy. In the case of head and neck cancer, there is no characteristic symptom at the initial stage, It is not easy to find early because there are many cases that have already proceeded to the latter period. Therefore, if you are diagnosed with cancer, you will have to remove some parts of your body such as the larynx, pharynx, tongue, and face if you are treated with radiotherapy or surgery. If you are cured, you will not only have serious aftereffects Since it is a site closely related to functions essential for daily living such as vocalization, breathing, chewing, and swallowing, it is often difficult for a patient to live a normal life due to the impairment of such function after surgery or radiation therapy, It is well known as a difficult cancer that is difficult to treat as compared with cancer. Therefore, chemotherapy is used in combination with radiation therapy to increase the effectiveness of radiation therapy, or to reduce the site of surgery through chemotherapy before surgery. In addition, recently, the rate of chemotherapy in head and neck cancer is increasing due to the active development of a target therapeutic agent specifically acting on cancer cells. Therefore, in order to treat head and neck cancer while reducing side effects and / or sequelae of cancer treatment, an effective treatment method for head and neck cancer is needed.

Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made in order to solve the above-mentioned problems in the prior art and provides a method of providing information on prediction of the cancer treatment effect of Pan-ErbB inhibitor including the step of confirming the activity of REV3L from a biological sample of a cancer patient It is an object of the present invention to provide a pharmaceutical composition for treating cancer, which comprises an inhibitor of REV3L (protein reversionless 3-like) and a Pan-ErbB inhibitor as an active ingredient.

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

Hereinafter, various embodiments described herein will be described with reference to the drawings. In the following description, for purposes of complete understanding of the present invention, various specific details are set forth, such as specific forms, compositions, and processes, and the like. However, certain embodiments may be practiced without one or more of these specific details, or with other known methods and forms. In other instances, well-known processes and techniques of manufacture are not described in any detail, in order not to unnecessarily obscure the present invention. Reference throughout this specification to "one embodiment" or "embodiment" means that a particular feature, form, composition, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Accordingly, the appearances of the phrase " in one embodiment "or" an embodiment "in various places throughout this specification are not necessarily indicative of the same embodiment of the present invention. In addition, a particular feature, form, composition, or characteristic may be combined in any suitable manner in one or more embodiments.

As used herein, "REV3L (Protein reversion-free 3-like) inhibitor" refers to all substances such as nucleic acids, compounds, and proteins that can inhibit the activity of REV3L, and is preferably specific for REV3L A silencing RNA, miRNA (microRNA), shRNA (short-hairpin RNA), an antisense-oligonucleotide, an antibody, an aptamer or the like, more preferably a nucleotide sequence of SEQ ID NO: But not limited to, the REV3L siRNA, or a substance capable of inhibiting the activity of REV3L. The activity inhibition method preferably inhibits the activity of REV3L by inhibiting the expression of mRNA and / or protein of REV3L or inhibiting the function of the produced REV3L protein, But is not limited thereto.

As used herein, the term "Pan-ErbB inhibitor" refers to a nucleic acid, a compound, a protein capable of inhibiting the activity of any one of ErbB family (ErbB-1, ErbB-2, ErbB-3 and ErbB- And any substance that can inhibit the activity of any one or more of the ErbB family is preferable. In the case of a substance capable of inhibiting the activity of at least one of dacomitinib, canertinib, apatinib, etc., or the ErbB family, none. The activity inhibition method is preferably not limited to a method of inhibiting the function of ErbB by binding to ErbB of any one of the ErbB family or a method of preventing the function of the ErbB family from being normally maintained in the body.

In the present specification, "the step of confirming the activity of REV3L" is a step of confirming whether the REV3L protein of the patient is normally functioning, preferably a method of confirming the expression level of REV3L, a method of confirming mutation of REV3L gene, A method for confirming the amount of the protein, and the like. However, the present invention is not limited thereto, so long as it is possible to confirm whether there is a REV3L protein normally functioning in the patient's body. The expression " method of confirming the expression level "refers to a comprehensive method for confirming the expression level of the REV3L gene in a sample. The method for measuring the expression level is a general method for measuring the amount of RNA and / There is no restriction.

As used herein, a "biological sample" refers to all samples isolated from a patient to measure the activity of REV3L, preferably blood, plasma, serum, cancer tissue, etc., Amount and / or amount of protein can be measured.

As used herein, the "method of providing information on the prediction of the cancer therapeutic effect" is a method of providing information on the therapeutic effect on the inhibitor when the Pan-ErbB inhibitor is used for cancer treatment, , Can effectively inhibit the progression of cancer, can kill cancer cells, and the like. Preferably, the mutation in the REV3L gene of a cancer patient does not normally result in the production of REV3L protein, or when the REV3L activity is expressed at a lower level as compared with the control sample, the information that the Pan-ErbB inhibitor can be used for effective cancer treatment Method, but is not limited thereto, as long as it can obtain information related to the cancer treatment effect of the Pan-ErbB inhibitor from the biological sample.

The present invention provides a pharmaceutical composition for administering a therapeutic combination comprising a REV3L (Protein reversionless 3-like) inhibitor and a Pan-ErbB inhibitor as an active ingredient.

In one embodiment of the present invention, the REV3L inhibitor may be a substance that inhibits the function of REV3L or inhibits the expression of REV3L, preferably siRNA (silencing RNA), miRNA RNA, shRNA (short hairpin RNA), antisense-oligonucleotide, antibody, aptamer and the like, but it is not limited thereto as long as the substance can regulate the REV3L protein from functioning normally.

In another embodiment of the present invention, the Pan-ErbB inhibitor is selected from the group consisting of ErbB-1, ErbB-2, ErbB-3 and ErbB- And can be preferably substances such as dacomitinib, canertinib, apatinib and the like which can be used for the treatment of cancer by inhibiting the function of the ErbB family Do not.

In another embodiment of the present invention, the cancer may preferably be head and neck cancer, stomach cancer, breast cancer, uterine cancer, brain cancer, rectal cancer, colon cancer, lung cancer, skin cancer, blood cancer, liver cancer, .

In the present invention, the pharmaceutical composition may be administered in combination with another anticancer agent, and thus can be effectively used to treat various types of cancer.

In the present invention, the pharmaceutical composition may be in the form of capsules, tablets, granules, injections, ointments, powders or beverages. The pharmaceutical composition may be a human. The pharmaceutical composition may be formulated in the form of oral preparations such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterilized injection solutions according to a conventional method. The pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be a binder, a lubricant, a disintegrant, an excipient, a solubilizing agent, a dispersing agent, a stabilizer, a suspending agent, a coloring matter, a perfume or the like in the case of oral administration. A solubilizing agent, an isotonic agent, a stabilizer and the like may be mixed and used. In the case of topical administration, a base, an excipient, a lubricant, a preservative and the like may be used. Formulations of the pharmaceutical compositions of the present invention may be prepared in a variety of ways by mixing with pharmaceutically acceptable carriers as described above. For example, oral administration may be in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. In the case of injections, they may be formulated in unit dosage ampoules or in multiple dosage forms have. Other, solutions, suspensions, tablets, capsules, sustained-release preparations and the like.

Examples of suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltoditol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil. Further, it may further include a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, an antiseptic, and the like.

The route of administration of the pharmaceutical compositions according to the present invention may be, but is not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, Sublingual or rectal. Oral or parenteral administration is preferred. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions of the present invention may also be administered in the form of suppositories for rectal administration.

The pharmaceutical composition of the present invention varies depending on various factors including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease to be prevented or treated. And the dose of the pharmaceutical composition may be appropriately selected by a person skilled in the art depending on the condition of the patient, the body weight, the degree of disease, the type of drug, the route of administration and the period of time, and may be 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way. The pharmaceutical composition according to the present invention can be formulated into pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.

In addition, the present invention provides a method for providing information on the prediction of cancer treatment effect of a Pan-ErbB inhibitor comprising the step of confirming the activity of REV3L from a biological sample of a cancer patient.

In one embodiment of the present invention, the method of providing information may further comprise comparing the level of the normal control sample.

In another embodiment of the present invention, the step of confirming the activity of the REV3L may be confirmed by measuring the level of expression of the REV3L or by measuring the function of the REV3L or by measuring the mutation of the REV3L gene It is possible. However, the present invention is not limited thereto, so long as the method can confirm that the patient's REV3L does not function properly in the body.

In another embodiment of the present invention, the biological sample may preferably be blood, plasma, serum, cancer tissue, etc., but is not limited thereto, as long as the activity of REV3L can be confirmed.

In addition, the present invention provides a method for screening a substance for use in combination with a Pan-ErbB inhibitor, comprising the steps of: (a) injecting a sample to be analyzed into a subject and confirming the activity of REV3L in the subject; And (b) when the activity of the REV3L of the subject is inhibited as compared with the normal control, the sample to be analyzed is judged to be a substance for co-administration, and a method for screening a substance for coadministration with a Pan-ErbB inhibitor ≪ / RTI > There is no limitation on the type of the sample to be analyzed, but it may be an oligonucleotide fragment, an antibody, a compound, or the like.

In one embodiment of the invention, the screening method may further comprise (c) treating the Pan-ErbB inhibitor and measuring the anti-cancer effect.

In another embodiment of the present invention, identifying the activity of the REV3L may be by measuring the level of expression of REV3L.

The information providing method for predicting the cancer treatment effect of the Pan-ErbB inhibitor according to the present invention can sensitively select patients that do not exhibit resistance to the Pan-ErbB inhibitor, and thus can exhibit a high therapeutic effect on the Pan-ErbB inhibitor In addition, it is expected that patients will be able to administer Pan-ErbB inhibitors by screening patients, thus enabling patient-tailored treatment and increasing treatment efficiency for Pan-ErbB inhibitors. In addition, the pharmaceutical composition for treating cancer comprising an REV3L (Protein reversion-less 3-like) inhibitor and a Pan-ErbB inhibitor according to the present invention as an active ingredient enhances the therapeutic effect of Pan-ErbB inhibitor-resistant patients It is expected to be possible.

FIG. 1 is a view showing a result of a total exome sequence analysis according to an embodiment of the present invention.
2 is a view showing a result of Western blotting according to an embodiment of the present invention.
FIG. 3 is a view showing the result of immunocytochemistry of BRCA1 protein according to an embodiment of the present invention.
FIG. 4 is a graph showing the cell death effect in the CAL33 cell line according to an embodiment of the present invention. FIG.
FIG. 5 is a graph showing the cell death effect in the FADU cell line and the MSKQLL2 cell line according to an embodiment of the present invention.
FIG. 6 is a view showing the combined administration effect of siREV3L and paclitaxel according to an embodiment of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. It will be apparent to those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Example 1: Whole Exomy Sequence Analysis

To confirm the genetic similarity of patients who respond effectively to treatment with Pan-ErbB inhibitors, 19 patients with metastatic head and neck cancer who received Dacomitinib, a Pand-ErbB inhibitor, And whole exome sequencing (WES) was performed. In order to perform the whole exon sequencing method, genomic DNA was extracted from patients blood according to the protocol using DNeasy Blood & Tissue Kit (Qiagen), and extracted DNA was extracted with Agilent SureSelect Human All Exome The entire exon sequence analysis was performed according to the protocol using 50Mb kit (Agilent Technologies) and Illumina HiSeq2000 platform. The Burrows-Wheeler aligner (Bioinformatics (2009) 25: 1754-1760) was used to align the sequence of the analyzed nucleotide sequence and the human reference genome contig (hg19) Genome Analysis Tool Kit (Nat. Genet (2011) 43: 491-498) was used for score recalibration and Picard and Samtools (Bioinformatics (2009) 25: 2078-2079 ) Was used. In addition, MuTect (Nat. Biotechnol (2013) 31: 213-219) for analysis of somatic single-nucleotide variants (SNVs) and insertion and deletion (INDELs) of somatic cell- And SomaticIndelDetector (Nat. Genet (2011) 43: 491-498) were used. For the functional analysis of somatic mutants, ANNOVAR package (Nucleic Acids Res. (2010) 38: e164) was used. The prevalence and rate of gene mutation were measured with sufficient sequencing coverage so that the average exon sum was 30 Mb. As a control group, somatic mutation data of 306 head and neck squamous cell carcinoma (HNSCC) were obtained from Cancer Genome Atlas consortium. The results are shown in Fig.

As shown in Figure 1, three of the seven patients who showed a therapeutic effect on the Pan-ErbB inhibitor had a REV3L (Protein reversionless 3-like) mutation, two of which were frameshift mutations, The name was a nonsense mutation. In addition, none of the patients who showed no therapeutic effect on Pan-ErbB inhibitors had mutations in REV3L. From the above results, it was confirmed that the therapeutic effect of REV3L on Pan-ErbB inhibitor can be demonstrated in the case of head and neck cancer in which the function of REV3L does not function normally due to a genetic variation in REV3L, . In addition, it was confirmed that the treatment method can be determined by selecting the patients showing the therapeutic effect on the Pan-ErbB inhibitor.

Example 2: Relationship between REV3L and Pan-ErbB Inhibitor

2.1. Cell cycle identification

In order to determine the cause of the therapeutic effect of Pan-ErbB inhibitor when the REV3L function of the cancer patient was inhibited, it was found that inhibition of the REV3L expression of cancer cells and the influence of the Pan-ErbB inhibitor on the cell cycle Respectively. In order to confirm the cell cycle inhibition effect, CAL33 cell line, which is one of the head and neck squamous cell carcinoma (HNSCC) cell lines, was cultured to 5 × 10 ⁷ cells, and then REV3L siRNA (IDT, CCCGAGUAAAUAGAGAAUUGUCCAA-3 'and 5 hours were further cultured for CAL33 cell line treated with scrambled siRNA, treated with each siRNA, incubated for 5 hours, exchanged with new medium for removal of siRNA, After incubation for 48 hours, the cells were harvested for cell cycle analysis, and the recovered cells were incubated for 1 hour at room temperature Were incubated for 30 min in PBS buffer containing 40 ug / mL propidium iodide (PI) and 100 ug / mL of RNase, Cells in the G0 / G1 phase and S phase were analyzed by FACS and DNA software program (FlowJo), and the percentage of cells in the G0 / G1 phase and S phase was measured using a FACS and DNA software program The same cell numbers were used for all the experimental groups in the cell cycle analysis.

Scrambled siRNA REV3L siRNA G0 / 1 S G0 / 1 (%) G0 / 1 S G0 / 1 (%) DMSO 35.34 36.48 49 29.76 44.68 40 Dacomitinib 0.5 uM 43.75 32.23 58 75.52 15.24 83 Dacomitinib 1uM 48.65 29.89 62 68.76 14.90 82

As shown in Table 1, when the Pan-ErbB inhibitor was treated with the inhibition of the expression of REV3L, 82-83% of the total cells as measured were cells of the G0 / 1 group and the Pan-ErbB inhibitor was not treated It was confirmed that the cells were two times or more of the G0 / 1 cells. On the other hand, in the case of Scrambled siRNA treated, the cells of G0 / 1 group accounted for 49% of the total cell counts in the absence of Pan-ErbB inhibitor, but when treated with Pan-ErbB inhibitor, Compared to cells not treated with 58% and 62%, respectively. From the above results, it was confirmed that when the Pan-ErbB inhibitor was treated with the REV3L-inhibited cancer cells, the cell cycle progression of the cancer cells was effectively inhibited and the cell division was reduced.

In order to confirm the cause of suppression of cell cycle progression, western blotting was performed using a part of cells recovered for cell cycle identification. The recovered cells were washed twice with cold PBS (phosphate buffered saline) buffer, and the proteins were separated by dissolving the cells using RIPA buffer. The separated proteins were analyzed by BCA assay The amount was measured. 20 ug of the protein obtained from each experimental group was separated by using 8-10% SDS-polyacrylamide gel and transferred to PVDF membrane by electricity. Protein-transferred PVDP membranes were treated with 5% skimmed milk at room temperature for 1 hour and then incubated with primary antibodies (Santa Cruz Biotechnology) for p21, p27, and beta-actin (control, control) And reacted together at 4 DEG C for 16 hours. The PVDP membrane reacted with the antibody was washed three times with TBST solution to remove unbound primary antibody and further reacted with secondary antibody (Santa Cruz Biotechnology) with HPR for 1 hour at room temperature. After completion of the reaction, the cells were washed with TBST solution to remove all secondary antibodies, treated with ECL solution, reacted for 3 minutes, and developed with Kodak X-OMAT AR Film. The results are shown in Fig.

As shown in FIG. 2, when the Pan-ErbB inhibitor was treated with the REV3L expression-suppressed cell line, the expression of p21 and p27 protein, which serve to arrest the cell cycle, was increased. From the above results, it was confirmed that when Pan-ErbB inhibitor was treated with cancer inhibiting REV3L function, the expression of p21 and p27 protein of cancer cells was increased, cell cycle progression was suppressed, and cell division was reduced.

2.2. Confirm homologous recombination

In general, when damage to DNA occurs, it is known that BRCA1 protein induces homologous recombination in cells and attempts to recover DNA. Therefore, in order to confirm whether homologous recombination occurs even when the Pan-ErbB inhibitor is treated in the cell line in which the expression of REV3L is inhibited, siRNA and docomitimin were treated in the same manner as in Example 2.1, (2008) 68 (22): 9141-9146 using BRCA1 protein immunocytochemistry. The results are shown in Fig.

As shown in Fig. 3, when the REV3L siRNA and the dacomitinib were co-administered, it was confirmed that the BRCA1 protein was accumulated in the cytoplasm. The above results show that treatment of Pan-ErbB inhibitor with REV3L-inhibited cells does not restore DNA to BRCA1 due to accumulation of BRCA1 in the cytoplasm, thereby weakening Pan-ErbB resistance and increasing anti-cancer effect .

2.3. Confirmation of anti-cancer effect

In order to confirm the therapeutic effect of Pan-ErbB inhibitor upon inhibition of REV3L function in cancer patients, inhibition of REV3L expression of cancer cells and inhibition of cancer cell death by Pan-ErbB inhibitor treatment were confirmed. The CAL33, FADU and MSKQLL2 cell lines were cultured to ⁵ × 10 ⁵ cells, respectively, and then treated with REV3L siRNA (IDT, SEQ ID NO: 1) and further cultured for 5 hours. As control, each cell line was treated with scrambled siRNA. Each siRNA was treated and incubated for 5 hours, then exchanged with fresh medium for removal of siRNA, followed by further incubation for 24 hours. The experimental group was treated with 0.001 uM or 0.1 uM of Dakomutinib and the same amount of DMSO as a control group . After incubation for 2 weeks, dead cells were removed using PBS and fixed in 10% neutral buffered formalin for 20 min at room temperature. After washing with PBS, the cells were stained with 0.005% crystal violet and observed with a microscope. The results are shown in Figures 4 and 5.

As shown in FIG. 4, 90% or more of head and neck cancer cells survive only the Pan-ErbB inhibitor, which is an anticancer drug, whereas the Pan-ErbB inhibitor inhibits the survival rate of cancer cells when the REV3L expression- 45%, respectively. The above results show that when the Pan-ErbB alone, which is used as a conventional anticancer agent, is administered alone, the cancer cell death effect is hardly observed, whereas when the Pan-ErbB inhibitor is administered to the cancer cell which inhibits REV3L function, .

Also, as shown in FIG. 5, it was confirmed that the inhibition of REV3L function in other cervical cancer cells and the cancer cell killing effect in case of treatment with Pan-ErbB inhibitor were increased.

In addition, when the Pan-ErbB inhibitor was changed to canertinib or apatinib in place of dacomitinib and the experiment was conducted in the same manner, Pan-ErbB The inhibitory effect of the inhibitor was increased.

These results suggest that REV3L genetic analysis of REH3L gene in patients with head and neck cancer, or REV3L functioning properly, predicts that cancer of the head and neck cancer with REV3L function is inhibited by Pan-ErbB inhibitor . In addition, it was confirmed that when Pan-ErbB inhibitor is administered together with REV3L inhibitor in head and neck cancer patients, the resistance to Pan-ErbB can be decreased and the effect of chemotherapy can be increased.

Example 3: Relationship between REV3L and other anticancer drugs

Paclitaxel and REV3L siRNA, which are well known anti-cancer agents as mitotic inhibitors, were co-administered in the same manner as in Example 2.3, in order to confirm whether REV3L also affects anticancer agents having mechanisms other than Pan-ErbB inhibitors Respectively. The results are shown in Fig.

As shown in FIG. 6, it was confirmed that the anticancer effect was not increased when the expression of REV3L was suppressed only by the anticancer effect by paclitaxel. These results indicate that REV3L expression inhibition synergizes with Pan-ErbB inhibitor but does not show efficacy against anticancer agents of other mechanisms.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

<110> Industry-Academic Cooperation Foundation, Yonsei University          JEUK Co., LTD. <120> Method for providing the information for predicting the cancer          treatment effect of Pan-ErbB inhibitors <130> DPB140057 <160> 1 <170> Kopatentin 2.0 <210> 1 <211> 25 <212> RNA <213> Artificial Sequence <220> <223> REV3L siRNA <400> 1 cccgaguaaa uagagaauug uccaa 25

Claims (15)

A method for providing information on the prediction of the cancer therapeutic effect of a Pan-ErbB inhibitor, comprising the step of confirming the activity of REV3L from a biological sample of a cancer patient. The method according to claim 1,
Wherein the information providing method further comprises the step of comparing the level with a level of a normal control sample. The method according to claim 1,
Wherein the step of confirming the activity of the REV3L measures the level of expression of the REV3L. The method according to claim 1,
Wherein the step of confirming the activity of the REV3L confirms mutation of the REV3L gene. The method according to claim 1,
Wherein the cancer is at least one selected from the group consisting of head and neck cancer, stomach cancer, breast cancer, uterine cancer, brain cancer, rectal cancer, colon cancer, lung cancer, skin cancer, blood cancer and liver cancer. The method according to claim 1,
Wherein the biological sample is blood, plasma, serum, or cancerous tissue. A pharmaceutical composition for administration in combination with a cancer treatment, which comprises an REV3L (Protein reversionless 3-like) inhibitor and a Pan-ErbB inhibitor as an active ingredient. 8. The method of claim 7,
Wherein said REV3L inhibitor inhibits the function of REV3L or inhibits REV3L expression. 8. The method of claim 7,
Wherein said REV3L inhibitor is an REV3L specific siRNA, miRNA, antibody, or squamous cell. 8. The method of claim 7,
Wherein the Pan-ErbB inhibitor binds to one or more ErbB selected from the group consisting of ErbB-1, ErbB-2, ErbB-3, and ErbB-4. 8. The method of claim 7,
Wherein the Pan-ErbB inhibitor is at least one selected from the group consisting of dacomitinib, canertinib, and apatinib. 8. The method of claim 7,
Wherein the cancer is at least one selected from the group consisting of head and neck cancer, stomach cancer, breast cancer, uterine cancer, brain cancer, rectal cancer, colon cancer, lung cancer, skin cancer, blood cancer and liver cancer. In a method for screening a substance for use in combination with a Pan-ErbB inhibitor,
(a) injecting a sample to be analyzed into a subject and confirming the activity of the REV3L of the subject; And
(b) a method for screening a substance to be coadministered with a Pan-ErbB inhibitor, comprising the step of determining that the sample to be analyzed is a co-administration substance when the activity of REV3L of the subject is inhibited compared with a normal control group . 14. The method of claim 13,
Wherein said screening method further comprises the step of (c) treating Pan-ErbB inhibitor and measuring anti-cancer effect. 14. The method of claim 13,
Wherein the step of confirming the activity of the REV3L measures the level of expression of the REV3L.

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