Methods for treatment of cancers that have acquired resistance to kinase inhibitors

Abstract

To provide a treatment method for cancers with acquired resistance that suppresses the onset of resistance to kinase inhibitors, which represents one of the greatest obstacles to effective treatment of cancer patients.SOLUTION: The present invention demonstrates that farnesyltransferase inhibition can prevent the emergence of resistance to kinase inhibitors in different oncogenic contexts. In particular, this invention measured in vitro efficacy of farnesyltransferase inhibitor (i.e. Tipifarnib) in combination with erlotinib in plural EGFR-mutated cell lines, showing that the combination efficiently eliminated all drug tolerant cells, and fully prevented emergence of resistant clones.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention is in the field of medicine, particularly oncology. [Background technology]

[0002] Lung cancer is the leading cause of cancer death worldwide. CLC) has recently been diagnosed with cancer-causing genes such as EGFR mutations, which have led to the development of targeted therapies. Identification of gene drivers and development of immune checkpoint inhibitors for cancer immunology We have benefited from two successive breakthroughs in our understanding of kuru.

[0003] First-generation EGFR-tyrosine kinase inhibitors such as erlotinib or gefitinib ( EGFR-TKIs are an effective treatment for NSCLC harboring EGFR activating mutations 2 . However, despite a 70% response rate, patients typically experience The median time to relapse was 12 months. The mechanism of acquired resistance was EGFR T790M mutation, MET 3 or HER2 4 Activation of bypass pathways, including epithelial-mesenchymal transition (EMT) 5 , and Transformation to small cell lung cancer 6 , etc. 7 These resistances are also due to the increase in downstream genes of EGFR. Growth / survival pathways, mainly PI3K / AKT, MEK / ERK, or STAT 8、9 Reactivation of Initially, it may be mediated by additional genetic alterations present in recurrent tumors. It was thought that targeting the tumors could solve the resistance problem. The heterogeneity of mutations within the T790M gates made this strategy ineffective. Treatment with osimertinib, a third-generation EGFR-TKI that effectively targets the PAR mutation Patients who received chemotherapy also showed the emergence of new resistance mechanisms (e.g., EGFR-C797S / G mutations). Relapse due to 10 .

[0004] Recent in vitro studies have demonstrated that EGFR-TKI resistance is generally expected to develop. Not only cannot be explained by the drug selection of existing resistant subclones, but also by slow cycle From a small population of drug-resistant cells (DTCs) that initially resist treatment by entering a clinging state This suggests that new 11 Some of these cells eventually enter the cell cycle. and eventually obtain a genetic mutation that allows sufficient proliferation ability to be restored. 12、13 DTC has been essentially described in the EGFR-mutated PC9 lung cell line. This is because (i) 1 μM of EGFR-TKI (this First, a dose of 50-100 times the IC50 of the cell line (which corresponds to the blood concentration in patients) was administered. (ii) a strong initial response at 5 days of treatment, corresponding to the presence of residual DTCs over several days The main effect observed in patients in vitro was a lag time of several weeks. These cells express either CD133 or CD24 as cancer stem cells. They are described as low-proliferative cells expressing markers and show epigenetic changes without genotypic alterations. I am receiving programming. 11、14 (iii) After several weeks of treatment, some of these cells , EGFR T790M Resistance mutations (in the case of first-generation EGFR-TKI treatment) or other New genetic modifications such as gene mutations can be obtained. 12、13 .

[0005] Other studies have shown that in NSCLC and in metastatic melanoma 15 , glioblastoma 16 , or acute bone myeloid leukemia 17 In other cancers, such as rheumatoid arthritis, there are also micro-cancerous lesions that occur in response to some anti-cancer treatments. It indicates the presence of a similar cellular state, also called residual disease (MRD). However, this particular condition remains poorly characterized, and it is unclear how tumor cells How do these DTCs evolve into the DTC state through molecular mechanisms and how do these DTCs evolve into resistance mutations? It remains to be seen how these cells may develop resistance in patients. Therefore, targeting these DTCs is not yet known. This is believed to be a new and promising approach to prevent the development of secondary resistance. , an accurate in vivo analysis of this specific condition, which is a prerequisite for the development of new therapeutic approaches. The phenotypic and molecular characterization of Summary of the Invention

[0006] As defined by the claims, the present invention provides a method for the treatment of cancer, comprising the steps of: The present invention relates to methods, pharmaceutical compositions, and kits for the treatment of cancer with anti-cancer drugs. [Brief description of the drawings]

[0007] [Figure 1]Figure 1 shows that FTi, but not GGTi, suppresses relapse in multiple TKI-sensitive models. GFP-transduced EGFR mutant cell lines were treated with FTi (tipifarnib, 1 μM), GGTi (GGTi-298, 1 μM), or TatC3 (2 μg / ml) (A-C), or erlotinib at 1 μM with or without tipifarnib at 0.1 μM (D-F), and response and relapse were followed by fluorescence detection (G-H). GFP-transduced H3122 (ALK-translocated NSCLC cell line) or A375 (BRAF-mutated melanoma cell line) were treated with tipifarnib at 0.1 μM in combination with alectinib (2 μM) or vemurafenib (5 μM), respectively, and response and relapse were followed by fluorescence detection. [Diagram 2] Figure 2 shows: (A) Change in tumor volume upon the indicated treatments; (B) Change in tumor size versus baseline in favorable response (45 days); (C) Kaplan-Meier progression-free survival plot; (D) Kaplan-Meier overall survival plot; (E) Change in mouse body size upon treatment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The first object of the present invention relates to a method for treating cancer in a subject in need of such treatment, The method includes administering to a subject a therapeutically effective The combination is administered to a subject.

[0009] A further object of the present invention is to prevent the development of cancer resistant to kinase inhibitors in a subject. The present invention relates to a method for delaying and / or preventing the onset of inflammatory bowel disease, the method comprising inhibiting farnesyltransferase. The method includes administering to a subject a therapeutically effective amount of a kinase inhibitor in combination with a cytotoxic agent.

[0010] As used herein, the term "resistance to a kinase inhibitor" refers to a kinase inhibitor that is resistant to a kinase inhibitor. In a very broad context, any compound that inhibits cell growth, kills cells, or induces one or more cell deaths. A reduction in the effectiveness of at least one kinase inhibitor that inhibits cell function and inhibits cell proliferation. to substances designed to inhibit, kill cells, or block one or more cellular functions The term is used to refer to the ability of cells to survive exposure to a certain amount of For example, it may be acquired by previous exposure to the substance, or it may be inherent or autonomic. Resistance exhibited by cells can be a result of the substance becoming completely ineffective against the cell. This may be complete, since it reduces the effectiveness of the substance, or it may be partial, since it reduces the effectiveness of the substance. Therefore, the term "resistant" refers to whether the disease has been cured before it develops or progresses. This refers to the frequent occurrence of cancer or the progression of cancer, regardless of disease.

[0011] It is a further object of the present invention to provide a method for treating a subject in need of treatment with a resistance to a kinase inhibitor. The present invention relates to a method for treating cancer in which a therapeutically effective amount of farnesyltransferase is administered. The method includes administering an enzyme inhibitor to a subject.

[0012] A further object of the present invention is to provide a method for the treatment of cancer by administering a kinase inhibitor to a subject suffering from cancer. The present invention relates to a method for inhibiting resistance to a steroid agonist, the method comprising administering a therapeutically effective amount of farnesyl transferase to a subject. The method includes administering to the subject an enzyme inhibitor.

[0013] A further object of the present invention is to provide a method for the treatment of cancer by administering a cyclophosphamide to a subject suffering from cancer as part of a treatment regimen. The present invention relates to a method for enhancing the efficacy of a kinase inhibitor, the method comprising administering to a patient a pharmaceutical composition comprising a kinase inhibitor in combination with the kinase inhibitor. The method includes administering to the subject a therapeutically effective amount of a farnesyltransferase inhibitor.

[0014] A further object of the present invention is to prevent the proliferation of cancer persister cells or the progression of cancer. By inhibiting or suppressing colony formation of persistent surviving cells, it is possible to prevent cancer recurrence and / or kinase US20130232633A1 - Use of farnesyl ether to prevent or delay the development of acquired resistance to treatment with farnesyl ether inhibitors - Google Patents The present study also relates to the use of cyclooxygenase inhibitors in cancer persister cells. The results may allow a complete response to cancer treatment. Transferase inhibitors may be able to eliminate cancer persister cells. Eliminate or reduce the population of persistent cancer cells and / or prevent cancer recurrence and / or The present invention relates to a method for preventing or delaying the development of acquired resistance to a cancer treatment, the method comprising: administering a therapeutically effective amount of a farnesyltransferase inhibitor, This eliminates or reduces the population of cancer persister cells. Kinase inhibitors may be useful in targeting "persistent" tumor cells, particularly kinase inhibitors. In the context of combination therapy with enzyme inhibitors, it is possible to prevent the emergence of drug-resistant clones. do.

[0015] As used herein, "persistent cells," "persistent cancer cells," "drug The terms "resistant persister," "DTP," and "DTP" refer to anti-cancer targeted therapeutic treatments, particularly kinase inhibitors. It is used to refer to a small population of cancer cells that remain viable upon treatment with a drug. More specifically, this is the effect of high concentrations of KI when used at a concentration 100-fold higher than the IC50. These cells are slow-growing and are almost completely resistant to treatment with enzyme inhibitors. Thus, the farnesyltransferase inhibitors of the present invention are As used herein, "drug resistance" refers to a compound that is capable of inhibiting or eradicating resistant growth persisters. The term "drug resistant persister" or "drug resistant cell" as used herein Thus, the proliferation of IL-17 cells was observed in the presence of continuous high-concentration cancer drug treatment, especially with kinase inhibitors. This refers to cancer cells that can

[0016] As used herein, the term "relapse" refers to a condition that has not yet progressed beyond an initial response (e.g., a complete The initial response period refers to the reappearance of cancer after a period of treatment (response or partial response). Lower than the value, e.g., 20%, 15%, 10%, 5%, 4%, 3%, 2%, or 1% The reappearance may be related to the level of cancer cells that are rapidly reduced. exceeding a certain value, for example, 20%, 15%, 10%, 5%, 4%, 3%, 2%, or 1%. More generally, a response (e.g., a complete response or A partial response (MSR) may involve the absence of detectable MRD (minimal residual disease). In this embodiment, the initial period of response is at least 1, 2, 3, 4, 6, 8, 10, or more or 12 months, or for at least 1, 2, 3, 4, or 5 years.

[0017] As used herein, the term "kinase inhibitor" refers to a kinase inhibitor that is known in the art. "refers to any compound now known or hereafter identified that, when administered to a subject, In some embodiments, the present invention includes any chemical moiety that inhibits a kinase pathway in cancer cells. In this case, kinase inhibitors are small organic molecules. Kinase inhibitors can be small molecular weight inhibitors, antibodies or are antibody fragments, antisense constructs, small inhibitory RNAs (i.e. ds These include, but are not limited to, RNA-mediated RNA interference (RNAi), and ribozymes. Kinase inhibitors are typically small organic molecules. The term refers to the inhibition of biological macromolecules (e.g., The preferred organic small molecules are 2000 Da or less, Most preferred is a size range of about 1000 Da or less.

[0018] In the present invention, the kinase inhibitor is a kinase inhibitor for treating cancer. The kinase may be a tyrosine kinase, a serine / threonine kinase, or a kinase having dual specificity. In certain embodiments, the kinase inhibitor is an inhibitor of the kinase activity in the treatment of cancer. It is known to be associated with acquired resistance. In a very particular embodiment, the kinase inhibitor is Associated with the emergence of persistent cancer cells upon treatment of cancer with kinase inhibitors.

[0019] In some embodiments, the kinase inhibitor is an EGFR family, ALK, B-Ra f, MEK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, IGF1R , c-Met, JAK family, PDGFRα and β, RET, AXL, c-KIT, Any of the kinases TrkA, TrkB, TrkC, ROS1, BTK, and Syk One may be targeted.

[0020] In some embodiments, the kinase inhibitor is a receptor tyrosine kinase inhibitor, particularly EGF R family, ALK, FGFR1, FGFR2, FGFR3, FGFR4, c-Met , RET, IGF1R, PDGFRα and β, c-KIT, FLT3, AXL, TrkA Inhibition of TrkA, TrkB, TrkC, and ROS1 It is a drug.

[0021] In some embodiments, the kinase inhibitor is EGFR, ALK, B-Raf, MEK , c-Met, JAK, PDGFRα and β, RET, and BTK. These are inhibitors that target tyrosine kinases that are involved in the development of ALK. The group of tyrosine kinases related to IL-1 are RET, ROS1, AXL, and the Trk family. It is a kinase.

[0022] EGFR kinase inhibitors are known. For example, There are articles published in Expert Opinion on Therapy. eutic Patents Dec 2002,Vol.12,No.12,Page s 1903-1907;Kane,Expert Opinion on Thera peutic Patents Feb 2006,Vol.16,No.2,Page s147-164;Traxler,Expert Opinion on Thera peutic patents Dec 1998,Vol.8,No.12,Page s1599-1625;Singh et al,Mini Rev Med Chem .2016;16(14):1134-66;Cheng et al, Curr Me d Chem.2016;23(29):3343-3359;Milik et al ,Eur J Med Chem.2017 Dec 15;142:131-151. ;Murtuza et al,Cancer Res.2019 Feb 15;79 (4):689-698;Tan et al, Onco Targets Ther. 2019 Jan 18;12:635-645;Roskoski, Pharmac ol Res.2019 Jan;139:395-411;Mountzios,An n Transl Med.2018 Apr;6(8):140;Tan et al ,Mol Cancer.2018 Feb 19;17(1):29), these publications See, for example, International Publication No. WO 190 / 06331, which is incorporated herein by reference, without being exhaustive. 10295, International Publication No. 19034075, International Publication No. 18129645, International Publication No. International Publication No. 18108064, International Publication No. 18050052, International Publication No. 18121758 No. 18218963, No. 17114383, No. 170 49992, International Publication No. 17008761, International Publication No. 17015363, International Publication No. International Publication No. 17016463, International Publication No. 17117680, International Publication No. 17205459 No. 16112847, No. 16054987, No. 160 70816, International Publication No. 16079763, International Publication No. 16125186, International Publication No. International Publication No. 16123706, International Publication No. 16050165, International Publication No. 15081822 No. 12167415, No. 13138495, No. 101 No. 29053, International Publication No. 10076764, International Publication No. 09143389, International Publication International Publication No. 05065687, International Publication No. 05018677, International Publication No. 05027972 In patent applications such as International Publication No. 04011461 and International Publication No. 0134574 have also published EGFR kinase inhibitors, and these publications are incorporated herein by reference. Specific examples of EGFR kinase inhibitors are disclosed in the table below.

[0023] ALK kinase inhibitors are known. For example, An article has been published (Beardslee et al, J Adv Prac t Oncol.2018 Jan-Feb;9(1):94-101;Pacenta et al,Drug Des Devel Ther.2018 Oct 23;1 2:3549-3561;Spagnuolo et al,Expert Opin Emerg Drugs.2018 Sep;23(3):231-241;Peter s et al,Curr Treat Options Oncol.2018 Ma y 28;19(7):37;Goldings et al,Mol Cancer. 2018 Feb 19;17(1):52;Karachaliou et al,E xpert Opin Investig Drugs.2017 Jun;26(6) :713-722;Liu et al,Curr Med Chem.2017;24 (6):590-613;Crescenzo et al,Curr Opin Ph armacol.2015 Aug;23:39-44;Sgambato et al ,Expert Rev Anticancer Ther.2018 Jan;18( 1):71-80;Michellys et al,Bioorg Med Chem Lett.2016 Feb 1;26(3):1090-1096;Straugh an et al,Curr Drug Targets.2016;17(6):73 9-45), which publications are incorporated herein by reference. Without the above, International Publication No. 04080980, International Publication No. 05016894, International Publication No. 0 5009389, International Publication No. 09117097, International Publication No. 09143389, International Publication No. 09132202, International Publication No. 10085597, International Publication No. 101436 64, International Publication No. 11138751, International Publication No. 12037155, International Publication No. No. 2017239, International Publication No. 12023597, International Publication No. 13013308, International Publication No. 14193932, International Publication No. 15031666, International Publication No. 151276 29, International Publication No. 15180685, International Publication No. 15194764, International Publication No. 7076355, International Publication No. 18001251, International Publication No. 18044767, In patent applications such as International Publication No. 18094134 and International Publication No. 18127184, ALK kinase inhibitors have been disclosed, and these disclosures are incorporated herein by reference. Specific examples of ALK kinase inhibitors are disclosed in the table below.

[0024] B-Raf kinase inhibitors are known. For example, An article has been published (Tsai et al., PNAS February ry 26,2008 105(8)3041-3046,Garnett and M arais,2004 Cancer cell,Volume6,Issue4,Pa ges313-319;Wilmott et al 2012, Cancer The rapy:Clinical,Volume18,Issue5;Fujimura e t al,Expert Opin Investig Drugs.2019 Feb ;28(2):143-148,Trojaniello et al,Expert Rev Clin Pharmacol.2019 Mar;12(3):259-26 6;Kakadia et al, Onco Targets Ther.2018 O ct 17;11:7095-7107;Roskoski,Pharmacol Re s.2018 Sep;135:239-258;Eroglu et al,Ther Adv Med Oncol.2016 Jan;8(1):48-56), these Publications are incorporated herein by reference. See, for example, International Publication No. 10 / 133,331, which is incorporated herein by reference, without limitation. 4164648, International Publication No. 14164648, International Publication No. 14206343, International Publication No. 13040515, International Publication No. 11147764, International Publication No. 110472 38, International Publication No. 11025968, International Publication No. 11025951, International Publication No. 1025938, International Publication No. 11025965, International Publication No. 11090738, International Publication No. 09143389, International Publication No. 09111280, International Publication No. 091112 79, International Publication No. 09111278, International Publication No. 09111277, International Publication No. 0 No. 8068507, International Publication No. 08020203, International Publication No. 07119055, International Publication No. 07113558, International Publication No. 07071963, International Publication No. 071135 57, International Publication No. 06079791, International Publication No. 06067446, International Publication No. 0 6040568, International Publication No. 06024836, International Publication No. 06024834, In patent applications such as International Publication No. 06003378 and International Publication No. 05123696, B-Raf kinase inhibitors have been disclosed, and these disclosures are incorporated herein by reference. Specific examples of ALK kinase inhibitors are disclosed in the table below.

[0025] Kinase inhibitors are inhibitors of MEK (mitogen-activated protein kinase kinase, also known as MAP2K, MP2K, MAPKK, MAPK / ERK kinase, JNK-activated kinase c-Jun N-terminal kinase kinase (JNKK), stress-activated protein kinase SAPKK; UniprotKB-Q02750 (MP2K1), P3 6507 (MP2K2), P46734 (MP2K3), P45985 (MP2K4), Q13163 (MP2K5), P52564 (MP2K6), O14733 (MP2K7) Preferably, the kinase inhibitor targets MEK-1 (also known as M AP2K1, MP2K1, MAPKK1 or MKK1) and / or ME K-2 (also known as MAP2K2, MP2K2, MAPKK2 or MKK2) Both MEK-1 and MEK-2 play specific roles in the MAPK / ERK cascade. MEK kinase inhibitors are known. For example, There is an article that publishes inhibitors (Kakadia et al., Onco Targets Ther.2018 Oct 17;11:7095-7107;St eeb et al,Eur J Cancer.2018 Nov;103:41-5 1;Sarkisian and Davar,Drug Des Devel The r.2018 Aug 20;12:2553-2565;Roskoski,Phar macol Res.2018 Sep;135:239-258;Eroglu et al,Ther Adv Med Oncol.2016 Jan;8(1):48- 56), which publications are incorporated herein by reference. In the present application, International Publication No. 15022662, International Publication No. 15058589, International Publication No. 140 No. 09319, International Publication No. 14204263, International Publication No. 13107283, International Publication International Publication No. 13136249, International Publication No. 13136254, International Publication No. 12095505 No. 12059041, No. 11047238, No. 110 47055, International Publication No. 11054828, International Publication No. 10017051, International Publication No. International Publication No. 10108652, International Publication No. 10121646, International Publication No. 10145197 No. 09129246, No. 09018238, No. 091 53554, International Publication No. 09018233, International Publication No. 09013462, International Publication International Publication No. 09093008, International Publication No. 08089459, International Publication No. 07014011 No. 07044515, No. 07071951, No. 070 22529, International Publication No. 07044084, International Publication No. 07088345, International Publication No. International Publication No. 07121481, International Publication No. 07123936, International Publication No. 06011466 No. 06011466, No. 06056427, No. 060 No. 58752, International Publication No. 06133417, International Publication No. 05023251, International Publication International Publication No. 05028426, International Publication No. 05051906, International Publication No. 05051300 No. 05051301, No. 05051302, No. 050 23759, International Publication No. 04005284, International Publication No. 03077855, International Publication No. International Publication No. 03077914, International Publication No. 02069960, International Publication No. 0168619 , International Publication No. 0176570, International Publication No. 0041994, International Publication No. 004202 2, WO 0042003, WO 0042002, WO 0056 706, WO 0068201, WO 9901426 and other patent applications We have also published MEK kinase inhibitors in other publications, and these publications are incorporated herein by reference. Specific examples of MEK kinase inhibitors are disclosed in the table below, which is incorporated herein by reference.

[0026] Kinase inhibitors include FGFR (fibroblast growth factor receptor, UniprotKB-P1 1362(FGFR1), P21802(FGFR2), P22607(FGFR3), P22455 (FGFR4)). FGFR kinase inhibitors are known. For example, there is an article disclosing such FGFR kinase inhibitors (Kat oh,Int J Mol Med.2016 Jul;38(1):3-15;Riz vi and Borad,J Gastrointest Oncol.2016 O ct;7(5):789-796;Tan et al, Onco Targets T her.2019 Jan 18;12:635-645,Shen et al,J Hematol Oncol.2018 Sep 19;11(1):120;Port a et al,Crit Rev Oncol Hematol.2017 May; 113:256-267;Cheng et al,Eur J Med Chem.2 017 Jan 27;126:476-490), these publications are hereby incorporated by reference. See, for example, International Publication No. WO 19034075, International Publication No. WO 2005 / 023661, which are incorporated herein by reference in their entirety, without being exhaustive. International Publication No. 19034076, International Publication No. 19001419, International Publication No. 18028438 No. 18049781, No. 18121650, No. 181 No. 53373, International Publication No. 18010514, International Publication No. 17028816, International Publication No. International Publication No. 17070708, International Publication No. 16091849, International Publication No. 16134320 No. 16054483, No. 15059668, No. 140 07951, International Publication No. 14026125, International Publication No. 14129477, International Publication No. International Publication No. 14162039, International Publication No. 14172644, International Publication No. 13108809 No. 13129369, No. 13144339, No. 131 79033, International Publication No. 13053983, International Publication No. 12008563, International Publication No. International Publication No. 12008564, International Publication No. 12047699, International Publication No. 09153592 No. 08078091, No. 08075068, No. 061 In patent applications such as International Publication No. 12479 and International Publication No. 04056822, FGFR kinase is also The present inventors have published novel enzyme inhibitors, which are incorporated herein by reference. Specific examples of FGFR kinase inhibitors are disclosed in the table below. Selectively one or more FGFR family members, particularly FGFR1, FGFR2, F It may be a member selected from GFR3, and FGFR4.

[0027] Kinase inhibitors include FLT3 (receptor tyrosine protein kinase FLT3, also known as FL cytokine receptor, fetal liver kinase-2 (FLK-2), Fms-like tyrosine kinase FLT-3, stem cell tyrosine kinase 1 (STK-1), or CD antigen:CD 135; also known as UniprotKB-P36888). FLT For example, such FLT3 kinase inhibitors have been disclosed. There is an article about this (Stone, Best Pract Res Clin Ha ematol.2018 Dec;31(4):401-404;Wu et al,J Hematol Oncol.2018 Dec 4;11(1):133;Shor t et al,Ther Adv Hematol.2019 Feb 15;10: 2040620719827310;Elshouryet al,Expert Re v Anticancer Ther.2019 Mar;19(3):273-286 ;Zhi et al,Eur J Med Chem.2018 Jul 15;15 5:303-315; Tiong IS, Wei AH, Genes Chromoso mes Cancer.2019 Mar 12,Gallogly and Laza rus,J Blood Med.2016 Apr 19;7:73-83;Pito ia and Jerkovich,Drug Des Devel Ther.201 6 Mar 11;10:1119-31), these publications are incorporated herein by reference. See, for example, International Publication No. WO 19034538 ... and International Publication No. WO 19034538, which are incorporated herein by reference, without being exhaustive. No. 7148440, International Publication No. 15056683, International Publication No. 13170671, International Publication No. 13124869, International Publication No. 13142382, International Publication No. 131575 40, International Publication No. 11086085, International Publication No. 09095399, International Publication No. 0 9143389, International Publication No. 08111441, International Publication No. 08046802, International Publication No. 06020145, International Publication No. 06106437, International Publication No. 061357 Patent applications such as No. 19 also disclose XX kinase inhibitors, and these disclosures are not publicly available. Specific examples of FLT3 kinase inhibitors include the following: Disclose in the table.

[0028] Kinase inhibitors act against the IGF1R (insulin-like growth factor 1 receptor, also known as insulin-like growth factor 1 receptor). Insulin-like growth factor I receptor (IGF-I receptor) or CD antigen: CD221; UniprotKB- It may target IGF1R kinase (also known as P08069 or C9J5X1). Inhibitors are well known. For example, here is an article disclosing such IGF1R kinase inhibitors: Published in (Qu et al, Oncotarget. 2017 Apr 25; 8(17):29501-29518;Chen et al, Curr Top Me d Chem.2017 Nov 20;17(28):3099-3130), these Publications such as International Publication No. WO 2005 / 023636 are incorporated herein by reference. See, for example, International Publication No. WO 2005 / 023636, without limitation. 16082713, International Publication No. 08076415, International Publication No. 08000922, International Publication No. 08076143, International Publication No. 07121279, International Publication No. 07083 017, International Publication No. 07075554, International Publication No. 06080450, International Publication No. No. 05095399, International Publication No. 05097800, International Publication No. 05037836, Patent applications such as International Publication No. WO 02092599 also disclose IGF1R kinase inhibitors. The publications cited above are incorporated herein by reference. Specific examples of enzyme inhibitors are disclosed in the table below.

[0029] Kinase inhibitors include c-Met (hepatocyte growth factor receptor, also known as HGF / SF receptor, Proto-oncogene c-Met, scatter factor receptor or tyrosine protein kinase Met;Uni It can target the c-Met kinase inhibitor (also known as protKB-P08581). For example, there is an article published disclosing one such c-Met kinase inhibitor. This has been reported in Zhang et al., Expert Opin Ther Pat. 2019 Jan;29(1):25-41;Gozdzik-Spychalska et al,Curr Treat Options Oncol.2014 Dec; 15(4):670-82;Bahrami et al, J Cell Physio l.2017 Oct;232(10):2657-2673;Zhang et al ,Eur J Med Chem.2016 Jan 27;108:495-504; Qi et al,World J Gastroenterol.2015 May 14;21(18):5445-53, which publications are incorporated herein by reference. See, for example, WO 18153293, WO 181 87355, International Publication No. 14000713, International Publication No. 14032498, International Publication No. International Publication No. 14067417, International Publication No. 14180182, International Publication No. 1307089 , International Publication No. 13107285, International Publication No. 13149581, International Publication No. 1200 6960, International Publication No. 12015677, International Publication No. 12034055, International Publication No. 12048258, International Publication No. 12075683, International Publication No. 11039527 , International Publication No. 11079142, International Publication No. 11121223, International Publication No. 1114 3646, International Publication No. 11149878, International Publication No. 10007317, International Publication No. 10007316, International Publication No. 10007318, International Publication No. 10019899 , International Publication No. 10059668, International Publication No. 10089508, International Publication No. 1008 9509, International Publication No. 09143389, International Publication No. 09143211, International Publication No. 09056692, International Publication No. 09093049, International Publication No. 09068955 , International Publication No. 13013308, International Publication No. 08023698, International Publication No. 0800 8310, International Publication No. 08102870, International Publication No. 07036630, International Publication No. 07066185, International Publication No. 07023768, International Publication No. 07002254 , International Publication No. 07002258, International Publication No. 07111904, International Publication No. 0610 4161, International Publication No. 05082854, International Publication No. 05082855, International Publication Patent applications such as No. 0160814 also disclose c-Met kinase inhibitors. , which publications are incorporated herein by reference. c-Met Kinase Inhibition Specific examples of agents are disclosed in the table below.

[0030] Kinase inhibitors include JAK (tyrosine protein kinase JAK2, also known as Januskin kinase It can target JAK kinase 2, also known as UniprotKB-O60674. Kinase inhibitors are well known. See, for example, US Pat. No. 6,333,663, which discloses such JAK kinase inhibitors. The results were published in He et al., Expert Opin Ther Pat. 2019 Feb;29(2):137-149;Hobbs et al,Hemat ol Oncol Clin North Am.2017 Aug;31(4):61 3-626;Senkevitch and Durum,Cytokine.2017 Oct;98:33-41;Leroy and Constantinescu,L eukemia.2017 May;31(5):1023-1038;Jin et al,Pathol Oncol Res.2019 Jan 31), these publications See, for example, International Publication No. WO 1903 / 023664, which is incorporated herein by reference, without limitation. 4153, International Publication No. 18215389, International Publication No. 18215390, International Publication No. 18204238, International Publication No. 17006968, International Publication No. 17079205 , International Publication No. 17091544, International Publication No. 17097224, International Publication No. 1712 9116, International Publication No. 17140254, International Publication No. 17215630, International Publication No. 16027195, International Publication No. 16032209, International Publication No. 16116025 , International Publication No. 16173484, International Publication No. 16191524, International Publication No. 1619 2563, International Publication No. 15174376, International Publication No. 15039612, International Publication No. 14111037, International Publication No. 14123167, International Publication No. 14146492 , International Publication No. 14186706, International Publication No. 13091539, International Publication No. 1318 8184, International Publication No. 11076419, International Publication No. 10085597, International Publication No. 10051549, International Publication No. 10083283, International Publication No. 10135621 , International Publication No. 10142752, International Publication No. 10149769, International Publication No. 1100 3065, International Publication No. 09132202, International Publication No. 09143389, International Publication No. 09062258, International Publication No. 09114512, International Publication No. 09145856 , International Publication No. 09155565, International Publication No. 09155551, International Publication No. 0804 7831, International Publication No. 08109943, International Publication No. 08116139, International Publication No. 08157207, International Publication No. 07070514, International Publication No. 07084557 , International Publication No. 07117494, International Publication No. 07007919, International Publication No. 0603 4116, International Publication No. 06056399, International Publication No. 06069080, International Publication No. 05095400, International Publication No. 04058753, International Publication No. 04041789 , International Publication No. 04041814, International Publication No. 04041810, International Publication No. 0310 In patent applications such as International Publication No. 1989 and International Publication No. 0152892, the authors also reported on JAK kinase inhibition. The JAK2A1 gene is a novel marker for the treatment of cancer, comprising the steps of: Specific examples of kinase inhibitors are disclosed in the table below.

[0031] Kinase inhibitors are used to treat PDGFR (platelet-derived growth factor receptor, also known as platelet-derived growth factor Receptor, CD140 antigen-like family member, UniprotKB-P16234( PGFRA, also known as P09619 (PGFRB), may be targeted. FR kinase inhibitors are known. For example, An article on this topic has been published (Roskoski, Pharmacol Res. 201 8 Mar;129:65-83;Andrick and Gandhi,Ann P harmacother.2017 Dec;51(12):1090-1098;Kh alique and Banerjee,Expert Opin Investig Drugs.2017 Sep;26(9):1073-1081;Miyamoto et al,Jpn J Clin Oncol.2018 Jun 1;48(6) :503-513;Gallogly and Lazarus,J Blood Me d.2016 Apr 19;7:73-83;Pitoia and Jerkovi ch,Drug Des Devel Ther.2016 Mar 11;10:11 19-31;Chen and Chen,Drug Des Devel Ther. 2015 Feb 9;9:773-9), which publications are incorporated herein by reference. See, for example, WO 11119894, WO 08 016192, International Publication No. 07004749, International Publication No. 03077892, International Publication No. 03077892, International Publication No. 0164200, International Publication No. 0125238 , WO 0172711, WO 0172758, WO 995711 Patent applications such as International Publication No. 7 and International Publication No. 9928304 also focus on PDGFR kinase inhibitors. Inhibitors thereof have been disclosed, and specific examples of PDGFR kinase inhibitors are disclosed in the table below.

[0032] Kinase inhibitors are a type of kinase inhibitor that inhibits the RET (proto-oncogene tyrosine protein kinase receptor, or cadherin family member 12, or the proto-oncogene c-Ret;UniprotK RET kinase inhibitors are well known. For example, there is an article that lists such RET kinase inhibitors (Ro skoski and Sadeghi-Nejad,Pharmacol Res.2 018 Feb;128:1-17;Zschaebitz and Gruellic h;Recent Results Cancer Res.2018;211:187 -198;Gruellich,Recent Results Cancer Res .2018;211:67-75;Pitoia and Jerkovich,Dru g Des Devel Ther.2016 Mar 11;10:1119-31) , which publications are incorporated herein by reference. International Publication No. 18071454, International Publication No. 18136663, International Publication No. 181366 61, International Publication No. 18071447, International Publication No. 18060714, International Publication No. 8022761, International Publication No. 18017983, International Publication No. 17146116, International Publication No. 17161269, International Publication No. 17146116, International Publication No. 170435 50, International Publication No. 17011776, International Publication No. 17026718, International Publication No. 4050781, International Publication No. 07136103, International Publication No. 06130673, etc. The RET kinase inhibitor has also been disclosed in the patent application. Certain examples are disclosed in the table below.

[0033] Kinase inhibitors include AXL (tyrosine protein kinase receptor UFO, also known as AXL It can target the oncogene, UniprotKB-P30530. XL kinase inhibitors are known. For example, such AXL kinase inhibitors have been published. An article on this topic has been published (Myers et al., J Med Chem. 2016 Apr 28;59(8):3593-608;Gruellich,Recent R Results Cancer Res.2018;211:67-75), these publications See, for example, International Publication No. WO 181 / 02363, which is incorporated herein by reference, without being exhaustive. No. 21228, International Publication No. 17059280, International Publication No. 17028797, International Publication No. International Publication No. 16166250, International Publication No. 16104617, International Publication No. 16097918 No. 16006706, No. 15143692, No. 151 19122, International Publication No. 15100117, International Publication No. 15068767, International Publication No. International Publication No. 15017607, International Publication No. 15012298, International Publication No. 13115280 No. 13074633, No. 12135800, No. 120 28332, International Publication No. 10090764, International Publication No. 10083465, International Publication No. International Publication No. 10005876, International Publication No. 10005879, International Publication No. 09127417 No. 09054864, No. 08128072, No. 080 98139, International Publication No. 08083353, International Publication No. 08083357, International Publication No. International Publication No. 08083354, International Publication No. 08083356, International Publication No. 08083367 No. 08080134, No. 08045978, No. 070 Patent applications such as No. 30680 also disclose AXL kinase inhibitors. The disclosure is incorporated herein by reference. Specific examples of AXL kinase inhibitors include The following table discloses:

[0034] Kinase inhibitors include c-KIT (Mast / Stem Cell Growth Factor Receptor Kit), and Piebald trait protein (PBT), proto-oncogene c-Kit , tyrosine protein kinase Kit, or p145c-Kit; UniprotKB- c-KIT kinase inhibitors are well known. For example, there is an article that discloses such a c-KIT kinase inhibitor ( Abbaspour Babaei et al, Drug Des Devel Th er.2016 Aug 1;10:2443-59,Zschaebitz and Gruellich;Recent Results Cancer Res.2018 ;211:187-198;Miyamoto et al,Jpn J Clin O ncol.2018 Jun 1;48(6):503-513;Chen et al ,Curr Top Med Chem.2017 Nov 20;17(28):30 99-3130;Gallogly and Lazarus,J Blood Med .2016 Apr 19;7:73-83;Pitoia and Jerkovic h,Drug Des Devel Ther.2016 Mar 11;10:111 9-31,Chen and Chen,Drug Des Devel Ther.2 015 Feb 9;9:773-9), which publications are incorporated herein by reference. See, for example, WO 19034128, WO 181 No. 12136, International Publication No. 18112140, International Publication No. 17167182, International Publication No. International Publication No. 17121444, International Publication No. 14202763, International Publication No. 13033116 No. 13033203, No. 13033167, No. 130 33070, International Publication No. 13014170, International Publication No. 09105712, International Publication International Publication No. 08011080, International Publication No. 08005877, International Publication No. 07124369 No. 07092403, No. 07038669, No. 070 26251, International Publication No. 06106437, International Publication No. 06135719, International Publication No. International Publication No. 06060381, International Publication No. 05073225, International Publication No. 05021531 No. 05021537, No. 05021544, No. 040 80462, International Publication No. 04014903, International Publication No. 03035049, International Publication No. International Publication No. 03002114, International Publication No. 03003006, International Publication No. 03004006 No. 6,239,663, and other patent applications also disclose c-KIT kinase inhibitors. Specific examples of c-KIT kinase inhibitors include those listed below, which are incorporated herein by reference. Disclosed in the table below.

[0035] Kinase inhibitors include Trk (tropomyosin receptor kinase), and high affinity neuronal growth factor receptor kinase (NGFR). Transforming tyrosine kinase receptor, or TRK Synkinase protein; UniprotKB-P04629 (Trk1), Q1662 0 (Trk2), Q16288 (Trk3). Kinase inhibitors are known. See, for example, US Pat. No. 6,333,663, which discloses such Trk kinase inhibitors. The results were published in Bhangoo and Sigal, Curr Oncol R ep.2019 Feb 4;21(2):14,Pacenta and Macy, Drug Des Devel Ther.2018 Oct 23;12:3549- 3561;Cocco et al,Nat Rev Clin Oncol.2018 Dec;15(12):731-747;Lange and Lo, Cancers (Basel).2018 Apr 4;10(4);Rolfo et al,Ex pert Opin Investig Drugs.2015;24(11):149 3-500), which publications are incorporated herein by reference. Without limiting the scope of the present invention, International Publication No. 18199166, International Publication No. 18079759, International Publication No. No. 17135399, International Publication No. 17087778, International Publication No. 17006953, International Publication No. 16164286, International Publication No. 16161572, International Publication No. 16116 900, International Publication No. 16036796, International Publication No. 16021629, International Publication No. 15200341, International Publication No. 15175788, International Publication No. 15143653, International Publication No. 15148350, International Publication No. 15148344, International Publication No. 15143 654, International Publication No. 15148373, International Publication No. 15148354, International Publication No. 15143652, International Publication No. 15089139, International Publication No. 15039334, International Publication No. 15042085, International Publication No. 15039333, International Publication No. 15017 533, International Publication No. 14129431, International Publication No. 14105958, International Publication No. No. 14078417, International Publication No. 14078408, International Publication No. 14078378, International Publication No. 14078372, International Publication No. 14078331, International Publication No. 14078 328, International Publication No. 14078325, International Publication No. 14078322, International Publication No. 14078323, International Publication No. 13183578, International Publication No. 13176970, International Publication No. 13161919, International Publication No. 13088257, International Publication No. 13088 256, International Publication No. 13009582, International Publication No. 12158413, International Publication No. No. 12137089, International Publication No. 12116217, International Publication No. 12034091, International Publication No. 12037155, International Publication No. 11006074, International Publication No. 10048 314, International Publication No. 10033941, International Publication No. 09054468, International Publication No. 08135785, International Publication No. 07123269, International Publication No. 06135719, International Publication No. 06123113, International Publication No. 06087538, International Publication No. 06087 530, International Publication No. 06082392, International Publication No. 05049033, International Publication No. Patent applications such as 03027111 also disclose Trk kinase inhibitors. These publications are incorporated herein by reference. Identification of Trk Kinase Inhibitors Examples are disclosed in the table below.

[0036] Kinase inhibitors are ROS1 (proto-oncogene tyrosine protein kinase ROS, also known as Proto-oncogene c-Ros, proto-oncogene c-Ros-1, receptor tyrosine kinase c-ro s oncogene 1, and c-Ros receptor tyrosine kinase; UniprotKB-P0 ROS1 kinase inhibitors are known. For example, there is an article that discloses such a ROS1 kinase inhibitor (Lin and Shaw,J Thorac Oncol.2017 Nov;12(11): 1611-1625;Facchinetti et al,Cancer Treat Rev.2017 Apr;55:83-95 ;Rolfo et al,Expe rt Opin Investig Drugs.2015;24(11):1493- 500,Yang and Gong,Expert Rev Clin Pharma col.2019 Mar;12(3):173-178,Liu et al. er Clin Risk Manag.2018 Jul 20;14:1247-1 252;Sgambato et al,Expert Rev Anticancer Ther. 2018 Jan;18(1):71-80), these publications are without reference See, for example, International Publication No. WO 13183578, which is incorporated herein by reference in its entirety, without any exhaustive description. , International Publication No. 13180183, International Publication No. 13158859, International Publication No. 1203 7155, International Publication No. 12005299, International Publication No. 14141129, International Publication No. 15144801, International Publication No. 15144799, International Publication No. 18170381 ROS1 kinase inhibitors have also been disclosed in patent applications such as Specific examples of ROS1 kinase inhibitors are listed in the table below. to disclose.

[0037] Kinase inhibitors include BTK (tyrosine protein kinase BTK, also known as agammaglobulin Antibody tyrosine kinase (ATK), precursor B cell kinase (BPK) and Bruton's type tyrosine kinase; also known as UniprotKB-Q06187) BTK kinase inhibitors are known. For example, An article on this topic has been published (Kim HO, Arch Pharm Res. 201 9 Feb;42(2):171-181;Lianget al,Eur J Med Chem.2018 May 10;151:315-326,Aw and Bro wn,Drugs Aging.2017 Jul;34(7):509-527;Wu et al,Oncotarget.2017 Jan 24;8(4):7201- 7207,Wu et al,J Hematol Oncol.2016 Sep 2 ;9(1):80), which publications are incorporated herein by reference. For example, without being exhaustive, International Publication No. 18002958, International Publication No. 18001331, International Publication No. 18009017, International Publication No. 18035080, International Publication No. 1808878 0, International Publication No. 18090792, International Publication No. 18095398, International Publication No. 18 133151, International Publication No. 18145525, International Publication No. 18154131, International Publication No. 18175512, International Publication No. 18192536, International Publication No. 1819253 2, International Publication No. 18196757, International Publication No. 18208132, International Publication No. 18 233655, International Publication No. 19034009, International Publication No. 17007987, International Publication No. 17046604, International Publication No. 17066014, International Publication No. 1707750 7, International Publication No. 17123695, International Publication No. 17127371, International Publication No. 17 128917, International Publication No. 17190048, International Publication No. 17106429, International Publication No. 16019233, International Publication No. 16057500, International Publication No. 1606522 2, International Publication No. 16066726, International Publication No. 16106628, International Publication No. 16 106626, WO 16106629, WO 16109215, WO Publication No. 16106627, International Publication No. 16106623, International Publication No. 1610662 4, International Publication No. 16106652, International Publication No. 16112637, International Publication No. 16 161571, International Publication No. 16161570, International Publication No. 16196776, International Publication No. 16196840, International Publication No. 16192074, International Publication No. 1621016 5, International Publication No. 16109220, International Publication No. 15017502, International Publication No. 15 002894, WO 15022926, WO 15048689, WO Publication No. 15048662, International Publication No. 15061247, International Publication No. 1508499 8, International Publication No. 15095102, International Publication No. 15095099, International Publication No. 15 116485, International Publication No. 15169233, International Publication No. 15165279, International Publication No. 15132799, International Publication No. 15039612, International Publication No. 1410475 7, International Publication No. 14113932, International Publication No. 14114185, International Publication No. 14 No. 113942, International Publication No. 14116504, International Publication No. 14130693, International Publication No. 14164558, International Publication No. 14151620, International Publication No. 1415211 4, International Publication No. 14161799, International Publication No. 14187319, International Publication No. 14 210255, International Publication No. 14005217, International Publication No. 14025976, International Publication No. 14039899, ​​International Publication No. 14055928, International Publication No. 1405593 4, International Publication No. 14068527, International Publication No. 14078578, International Publication No. 14 082598, International Publication No. 14082598, International Publication No. 13067264, International Publication No. 13081016, International Publication No. 13102059, International Publication No. 1311638 2, International Publication No. 13148603, International Publication No. 13152135, International Publication No. 13 185084, International Publication No. 13067277, International Publication No. 13067274, International Publication No. 13059738, International Publication No. 13010869, International Publication No. 1301038 0, International Publication No. 13010868, International Publication No. 12170976, International Publication No. 12 135801, International Publication No. 12021444, International Publication No. 11153514, International Publication No. 11152351, International Publication No. 11029043, International Publication No. 1102904 6, International Publication No. 10126960, International Publication No. 10056875, International Publication No. 10 009342, WO 09156284, WO 09098144, WO Publication No. 09053269, International Publication No. 08121742, International Publication No. 0803921 Patent applications such as International Publication No. 9954286 and International Patent Application Publication No. 8 also disclose BTK kinase inhibitors. The disclosures of which are incorporated herein by reference. Specific examples of enzyme inhibitors are disclosed in the table below.

[0038] Kinase inhibitors include Syk (tyrosine protein kinase SYK, also known as spleen tyrosine kinase The kinase, p72-Syk; also known as UniprotKB-P43405) was targeted. Syk kinase inhibitors are known. For example, such Syk kinase inhibitors There is an article that discloses the agent (Bartaula-Brevik et al. ,Expert Opin Investig Drugs.2018 Apr;27( 4):377-387;Liu and Mamorska-Dyga,J Hemat ol Oncol.2017;10: 145,Geahlen,Trends Pha rmacol Sci.2014 Aug;35(8):414-22;Norman Expert Opin Ther Pat.2014 May;24(5):573- 95), which publications are incorporated herein by reference. In the International Publication No. 19034153, International Publication No. 18053189, International Publication No. 180 No. 53190, International Publication No. 18108083, International Publication No. 18228475, International Publication No. International Publication No. 17046302, International Publication No. 16010809, International Publication No. 15138273 No. 15140051, No. 15140054, No. 151 40055, International Publication No. 15144614, International Publication No. 15017610, International Publication No. WO 15061369, WO 15094997, WO 15095444 No. 15095445, No. 15100217, No. 140 No. 51654, International Publication No. 14048065, International Publication No. 14060371, International Publication International Publication No. 14064134, International Publication No. 14074422, International Publication No. 14086032 No. 14093191, No. 14100314, No. 141 76210, International Publication No. 14176216, International Publication No. 14023385, International Publication No. International Publication No. 14027300, International Publication No. 14031438, International Publication No. 14029732 No. 14045029, No. 13192125, No. 131 92128, International Publication No. 13192098, International Publication No. 13192088, International Publication No. International Publication No. 13047813, International Publication No. 13052391, International Publication No. 13052394 No. 13052393, No. 13064445, No. 130 99041, International Publication No. 13104573, International Publication No. 13104575, International Publication No. International Publication No. 13109882, International Publication No. 13124026, International Publication No. 13126132 No. 13124025, No. 12002577, No. 120 25187, International Publication No. 12025186, International Publication No. 12061418, International Publication No. International Publication No. 12123311, International Publication No. 12123312, International Publication No. 12130780 No. 12151137, No. 12154519, No. 121 No. 54520, International Publication No. 12154518, International Publication No. 12167423, International Publication No. WO 12167733, WO 11086085, WO 11014795 No. 11014515, No. 11075515, No. 110 75560, International Publication No. 11079051, International Publication No. 11092128, International Publication No. International Publication No. 11112995, International Publication No. 11117160, International Publication No. 11134971 No. 11144584, No. 11144585, No. 100 68257, International Publication No. 10068258, International Publication No. 10097248, International Publication No. International Publication No. 10147898, International Publication No. 09131687, International Publication No. 09136995 No. 09145856, No. 09031011, No. 080 33798, International Publication No. 07129226, International Publication No. 07042298, International Publication No. International Publication No. 07042299, International Publication No. 07028445, International Publication No. 07009681 No. 07009681, No. 07085540, No. 060 93247, International Publication No. 05033316, International Publication No. 05026158, International Publication No. International Publication No. 03063794, International Publication No. 03057695, International Publication No. 0183485 , International Publication No. 0147922, International Publication No. 0109134, International Publication No. 007511 In patent applications such as No. 3, Syk kinase inhibitors have been disclosed. Specific examples of Syk kinase inhibitors are listed in the table below. to disclose.

[0039] In very particular embodiments, the kinase inhibitor can be selected from the following table: do. [Table 1] JPEG2025038167000002.jpg161156

[0040] In some embodiments, the kinase inhibitor is an EGFR inhibitor. For example, this may be Gefitinib, erlotinib, lapatinib, vandetanib, afatinib, osimertinib , neratinib, dacomitinib, brigutinib, canertinib, nacotinib, nazartinib The agent can be selected from the group consisting of rifabutinib, pelitinib, rociletinib, and icotinib.

[0041] In some embodiments, the subject is diagnosed with a cancer that exhibits increased activity of the MAPK pathway (i.e., As used herein, the term "cancer associated with activation of the APK pathway" refers to a cancer that is caused by a cancer-related condition. In one embodiment, the increase in expression or activity is at least 1% relative to a reference expression level or a reference activity level. 0%, at least 20%, at least 30%, at least 40%, at least 50%, an expression level that is at least 100%, at least 200%, at least 300% or higher; The expression level of a given component in the MAPK pathway is increased. Methods for determining whether a component is a nucleotide sequence or not are well known in the art, and the corresponding component mRNA Level-based methods (e.g., Northern blots, RT-PCR, etc.), and Methods based on determining the protein levels of the corresponding components (e.g., ELISA, Western blots, etc.) to determine whether the activity of one or more components in the MAPK pathway is increased. Methods for determining the activity of various components are based on the determination of activity and are well known to those skilled in the art. A suitable method for determining the activity of the PK pathway is, for example, phosphorylated ERK (MAPK) protein. Includes detection of quality and the ratio of phosphorylated ERK to ERK.

[0042] In some embodiments, the subject has an at least one abnormality in a protein involved in the MAPK pathway. Typically, the above mentioned The tyrosine kinase receptors (e.g., FGFR1, FGFR2, FGFR3, EGFR , HER2, IGF-1R, cMET, etc.), BRAF, RAS, CRAF, CCND1 , CDK4, MAP2K1, MAP2K2, NRAS, KRAS, HRAS, PTEN, It is characterized by at least one mutation in PIK3CA, and P16.

[0043] In some embodiments, the subject is afflicted with an EGFR mutant cancer. As used herein, the term "EGFR" is intended to have its common meaning in the art. and stands for epidermal growth factor receptor. EGFR is an extracellular protein ligand for epidermal growth factor receptor. It is a well-known transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family). The epidermal growth factor receptor is a member of four closely related receptor tyrosine kinases, EGFR. FR (ErbB-1), HER2 / neu (ErbB-2), Her3 (ErbB-3) , and the ErbB family of receptors, including the Her4 (ErbB-4) subfamily. As used herein, the table "EGFR mutant cancer" includes Currently, it refers to cancers in which the cancer cells contain activating mutations in EGFR. Numerous mutations are known, typically L858R, T790M, and C797S. include.

[0044] In some embodiments, the subject is afflicted with an ALK mutant cancer. As used herein, the term "ALK" has its ordinary meaning in the art. It refers to the anaplastic lymphoma kinase (ALK) which is involved in cell proliferation. Mutated (altered) forms of this protein are found in neuroblastoma, non-small cell lung cancer, and undifferentiated These changes are seen in several types of cancer, including idiopathic large cell lymphoma. As used herein, "ALK mutations" may increase the proliferation of cancer cells. The term "ALK-positive" refers to cancers whose cancer cells contain activating mutations in ALK. Numerous mutations in ALK are known. ALK mutations are well known, and rearrangements (AL There are three types of ALK mutations: ALK-KR, amplification (ALK-A), and point mutation. C1156Y, L1196M, G1269A, F1174L, 1151Tins, L 1152R, S1206Y, I1171T, G1202, D1203N, and V1180 Multiple point mutations that confer drug resistance, including L, have been identified.

[0045] In some embodiments, the subject is afflicted with a RAS mutant cancer. As used herein, the term "RAS" refers to any member of the RAS family of proteins. The Ras family proteins correspond to HRAS, KR AS, and NRAS, and DIRAS1;DIRAS2;DIRAS3;ERAS;G EM;MRAS;NKIRAS1;NKIRAS2;NRAS;RALA;RALB;R AP1A;RAP1B;RAP2A;RAP2B;RAP2C;RASD1;RASD2 ;RASL10A;RASL10B;RASL11A;RASL11B;RASL12; REM1;REM2;RERG;RERGL;RRAD;RRAS;RRAS2 and other members of the subfamily (Wennerber, g et al.,The Ras superfamily at a glance , J. Cell.Sci.,2005,118(Pt 5),843-846). Therefore, the expression "mutated RAS cancer" means that cancer cells have a mutation in the Ras protein that activates the In particular, the subject is afflicted with an NRAS mutant cancer. Numerous mutations in RAS are known, including Q61R, Q61K, Q61H, and Q6 1L, Q61N, Q61E, Q61P, A146T, A146P, or A146V are typical This includes.

[0046] In some embodiments, the subject is afflicted with a RAF mutant cancer. As used herein, the term "RAF" refers to any member of the Raf family of proteins. RAF family proteins correspond to A-RAF, B-RAF, and their mutant forms. -RAF, and C-RAF. The term "AF cancer" refers to cancer cells that contain activating mutations in the Raf protein. In particular, the subject has a BRAF-mutated cancer. Mutations are known, especially the V600E mutation. Other mutations include R461I, I462S, G463E, G463V, G465A, and G465 E, G465V, G468A, G468E, N580S, E585K, D593V, F5 94L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, V600E, and A727V, and most of these mutations were in the N-lobe The glycine-rich P loop and the activation segment and adjacent regions are clustered together. As known in the art, multiple PCR and / or sequencing based methods are used to generate Several methods are known to be used for detecting mutations in the MAPK pathway, including ose et al., Cancer Research 62:6997-7000(2002), Solit et al., Cancer Research 70(14):5901-5911( 1010), Xu et al., Cancer research 63:4561-4567(2 003), and U.S. Pat. No. 7,745,128. Several research articles and US patents, as well as several commercially available kits (Dxs Diagnosti Innovations, Applied Biosystems, and Quest The diagnostics are shown in Table 1.

[0047] Also encompassed within the scope of the present invention are various cancers, including, but not limited to: Carcinomas, such as bladder cancer (including advanced and metastatic bladder cancer), breast cancer, colon cancer (including colorectal cancer), kidney cancer, liver cancer, lung cancer (including small cell lung cancer and small cell lung cancer and lung adenocarcinoma) , ovarian cancer, prostate cancer, testicular cancer, genitourinary cancer, lymphatic system cancer, rectal cancer, laryngeal cancer, pancreatic cancer ( pancreatic exocrine cancer), esophageal cancer, stomach cancer, gallbladder cancer, cervical cancer, thyroid cancer, and skin cancer (squamous hematopoietic tumors of lymphoid lineage, e.g., leukemia, acute lymphocytic leukemia, acute Myeloid lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma (cutaneous T-cell lymphoma or Peripheral T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell Lymphoma, histiocytic lymphoma, and Burkitt's lymphoma; hematopoietic tumors of myeloid lineage, e.g. For example, acute and chronic myeloid leukemia, myelodysplastic syndromes, myeloid leukemia, and promyelocytic leukemia; tumors of the central and peripheral nervous system, such as astrocytoma, neuroblastoma, glioma, and and schwannomas; tumors of mesenchymal origin, such as fibrosarcoma, rhabdomyosarcoma, and osteosarcoma; other Tumors, such as melanoma, xeroderma pigmentosum, keratoacanthoma, seminoma, follicular thyroid carcinoma, and melanoma, unresectable stage III or IV malignant melanoma, squamous cell carcinoma, Small cell lung cancer, non-small cell lung cancer, glioma, gastrointestinal cancer, kidney cancer, ovarian cancer, liver cancer , colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, pancreatic Pancreatic cancer, glioblastoma multiforme, cervical cancer, gastric cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, and head and neck cancer, retinoblastoma, gastric cancer, germ cell tumors, bone cancer, bone tumors, adult malignant fibrous carcinoma of bone Histiocytoma; childhood malignant fibrous histiocytoma of bone; sarcoma; childhood sarcoma; myelodysplastic syndrome; neuroblastoma Testicular germ cell tumors, intraocular melanoma, myelodysplastic syndromes, myelodysplastic / myeloproliferative disorders The patient was diagnosed with synovial sarcoma.

[0048] In some embodiments, the cancer is a solid tumor. For example, the cancer is a sarcoma or osteosarcoma, For example, Kaposi's sarcoma, AIDS-associated Kaposi's sarcoma, melanoma, particularly uveal melanoma, and head and neck tumors. Cervix, kidneys, ovaries, pancreas, prostate, thyroid, lungs, esophagus, breasts, especially triple negative breasts Cancer (TNBC), bladder, colorectal, liver and bile duct, uterine, appendix, and cervical cancer; The cancer may be testicular cancer, gastrointestinal cancer, and endometrial and peritoneal cancer. , sarcoma, melanoma, especially uveal melanoma, as well as head and neck, kidney, ovary, pancreas, prostate, thyroid Cancer of the bladder, colon, rectum, liver, cervix, and esophagus, especially (TNBC), and endometrial and peritoneal cancers.

[0049] In some embodiments, the cancer is selected from the group consisting of leukemia, lymphoma, sarcoma, melanoma, and head and neck cancer. Kidneys, ovaries, pancreas, prostate, thyroid, lungs, esophagus, breast, bladder, brain, colorectal, liver, and The cancer may be selected from the group consisting of cancer of the cervix.

[0050] In some embodiments, the cancer is lung cancer, particularly non-small cell lung cancer, leukemia, particularly acute bone marrow cancer, Myelogenous leukemia, chronic lymphocytic leukemia, lymphoma, especially peripheral T-cell lymphoma, chronic myelogenous Leukemia, squamous cell carcinoma of the head and neck, advanced melanoma with BRAF mutations, colorectal cancer, gastrointestinal cancer Tumors and stromal tumors of the breast, especially HER2 + Breast cancer, thyroid cancer, especially advanced medullary thyroid cancer , kidney cancer, especially renal cell carcinoma, prostate cancer, glioma, pancreatic cancer, especially pancreatic neuroendocrine carcinoma, It may be selected from the group consisting of multiple myeloma, and liver cancer, particularly hepatocellular carcinoma.

[0051] In particular, the subject is suffering from lung cancer. As used herein, "lung cancer" refers to The term has its ordinary meaning in the art and may in some cases lead to metastasis. It refers to a disease in lung tissue that involves uncontrolled cell proliferation. Lung cancer is a carcinoma of the lung that originates from epithelial cells. The main types of lung cancer are small cell lung cancer (SCLC). In certain embodiments, the subject has non-small cell lung cancer (NSCLC). As used herein, the term "non-small cell lung cancer" refers to The term is also known as non-small cell lung cancer (NSCLC) and refers to non-small cell lung cancer (SCLC). It refers to superficial lung cancer. There are three main subtypes: adenocarcinoma, squamous cell carcinoma, and large cell lung cancer. Other less common types of non-small cell lung cancer are pleomorphic, carcinoid, and pulmonary This includes adenocarcinoma of the esophagus and unclassified carcinoma. Adenocarcinoma accounts for approximately 40% of lung cancers and is most commonly seen in people who have never smoked. It is the most common type of lung cancer in adults. Squamous cell carcinoma accounts for approximately 25% of lung cancers. Squamous cell carcinoma of the lung is more common in men than in women and is more common than other types of lung cancer. The risk of developing squamous cell carcinoma of the lung is at least 1.5%. There are four variants: papillary, small cell, clear cell, and basaloid. Large cell lung cancer is a heterogeneous group of malignant neoplasms that originate in cancerous epithelial cells in the lung. The cancer is a carcinoma that does not have the light microscopic features of small cell carcinoma, squamous cell carcinoma, or adenocarcinoma. NS CLC is staged using the Tumor-Node-Metastasis (TNM) staging system. Spira J & Ettinger, DSMultidiscip linear management of lung cancer,N Engl J Med,350:382-(2004)(Spira);Greene FL ,Page DL,Fleming ID,Fritz AG,Balch C M, Haller DG, et al. (eds). AJCC Cancer Staging Manual.6th edition.New York: Springer-Ve rlag,2002:167-77(hereafter Greene);Sobin LH,Wit tekind CH (eds).International Union Aga inst Cancer.TNM classification of malign ant tumours.6th edition.New York:Wiley-L iss (2002) (hereinafter Sobin). In this study, lung cancer was classified as one of the previously mentioned stages (e.g., occult, stage 0, stage IA, Stage IB, Stage IIA, Stage IIB, Stage IIIA, Stage I More specifically, the subject can be stratified into stage IIB, stage IV, or stage IV. Patients with EGFR-mutated NSCLC or ALK-mutated NSCLC such as

[0052] In particular, the subject is suffering from melanoma, in particular metastatic melanoma. Thus, "melanoma" is a tumor caused by the growth of a tumor arising from the melanocytic system of the skin and other organs. Most melanocytes occur in the skin, but they can also occur in the meninges, gastrointestinal tract, and It can also be found in lymph nodes and the eyes. When melanoma occurs in the skin, it is called cutaneous melanoma. Melanoma can also occur in the eye, where it is called ocular or intraocular melanoma. It rarely occurs in the meninges, gastrointestinal tract, lymph nodes, or other areas where melanocytes are found. Between 40 and 60% of melanomas harbor activating BRAF mutations.

[0053] In some embodiments, when the kinase inhibitor is an EGFR inhibitor, the cancer is preferably or lung cancer, especially non-small cell lung cancer, pancreatic cancer, breast cancer, especially early stage breast cancer, and thyroid cancer. thyroid cancer, especially medullary thyroid cancer, colorectal cancer, especially metastatic or advanced colorectal cancer, head and neck carcinoma and squamous cell carcinoma, and glioma. The kinase inhibitor is an ALK inhibitor. In the case of a cancer, the cancer is preferably non-small cell lung cancer. When the therapeutic agent is a cancer, the cancer is preferably melanoma, lung cancer, colorectal cancer, and gastrointestinal stromal cancer. When the kinase inhibitor is a MEK inhibitor, the cancer is preferably selected from the group consisting of or melanoma or lung cancer. When the kinase inhibitor is an FGFR inhibitor, the cancer is , preferably selected from the group consisting of thyroid cancer, colorectal cancer, and gastrointestinal stromal cancer. When the kinase inhibitor is an FLT3 inhibitor, the cancer is preferably kidney cancer, pancreatic cancer, or In particular, pancreatic neuroendocrine tumors, gastrointestinal stromal cancer, multiple myeloma, prostate cancer, leukemia, etc. For example, the present invention is directed to a method for treating acute myeloid leukemia, chronic lymphocytic leukemia, and lymphoma. When the kinase inhibitor is a JAK inhibitor, the cancer is preferably lymphoma, particularly terminal cancer. From peripheral T-cell lymphoma, myeloproliferative neoplasms, multiple myeloma, pancreatic cancer, and prostate cancer When the kinase inhibitor is a PDGFR inhibitor, the cancer is preferably Leukemia, e.g. Philadelphia chromosome positive chronic myeloid leukemia, gastrointestinal stromal cancer, Myelodysplastic and myeloproliferative disorders, colorectal cancer, renal cancer, pancreatic cancer, especially pancreatic neuroendocrine cancer The kinase inhibitor is selected from the group consisting of tumors, liver cancer, breast cancer, and thyroid cancer. In the case of a RET inhibitor, the cancer is preferably kidney cancer or thyroid cancer, e.g. When the kinase inhibitor is an AXL inhibitor, the cancer is preferably a myocardial infarction cancer. Hematologic diseases, particularly acute leukemia, such as acute myeloid leukemia or Philadelphia chromosome positive chronic osteoporosis The cancer is selected from the group consisting of myeloid leukemia, renal cancer, and lung cancer, e.g., NSCLC. When the kinase inhibitor is a Trk inhibitor, the cancer is preferably a metastatic solid cancer. When the enzyme inhibitor is a ROS1 inhibitor, the cancer is preferably lung cancer, e.g., NSC LC, and renal cancer. When the kinase inhibitor is a BTK inhibitor, In this case, the cancer is preferably a B-cell cancer, such as chronic lymphocytic leukemia (CLL), and non- Hodgkin's lymphoma. When the kinase inhibitor is a Syk inhibitor, The cancer is preferably a lymphoma, in particular a peripheral T-cell lymphoma.

[0054] As used herein, the term "farnesyltransferase inhibitors" refers to The term refers to a molecule that inhibits the enzymatic catalytic transfer of a farnesyl residue to a substrate. In the present specification, the term "substrate to be farnesylated" can always be understood in a broad sense. A polypeptide is typically at least four amino acids in length. The polypeptide to be catalyzed and farnesylated preferably contains a CAAX sequence motif. where C is a cysteine ​​moiety, A is an aliphatic amino acid moiety, and X is a farnesyl group. As used herein, the term "amino acid" refers to a sequence that is specific to a particular enzyme. Thus, the enzymatic catalytic transfer of the farnesyl residue occurs when the farnesyl residue is a substrate, preferably represents a biochemical reaction that transfers a farnesyl residue to a polypeptide. The enzyme that does this is called farnesyltransferase. In this case, typically, the activation The activated farnesol is preferably farnesyl diphosphate ( Farnesyl pyrophosphate (FPP). Typically, the polypeptide corresponding to the substrate is Farnesylated at the cysteine ​​moiety, thus giving rise to a thiol ester The terms "thiol ester" and "thioester" are interchangeable and refer to R1-CO represents the group -S-R2, where the thiol ester also represents the ester R1-COH=SR 2 tautomeric form. Preferably, a cysteine ​​that can be farnesylated The moiety is located close to the C-terminus of the protein. The cysteine ​​moiety of F is farnesylated, where C is the cysteine ​​moiety and A is the aliphatic alkyl group. amino acid moiety, and X is another amino acid moiety specified by the enzyme that catalyzes farnesylation. Equivalent to minutes.

[0055] The enzyme that catalyzes farnesylation is preferably farnesyltransferase (F Tase), which has the enzyme classification number EC 2.5.1.X, more preferably EC 2. 5.1.29, EC 2.5.1.58, or EC 2.5.1.59, even more preferably Prenyltransferase having EC 2.5.1.29 or EC 2.5.1.58 The enzyme typically binds one or more zinc ions (Zn2+). In addition, geranylgeranyltransferase, in the context of the present invention, is a farnesyltransferase. It may also be effective as a farnesyltransferase, because this enzyme also catalyzes the conversion of certain polypeptides to farnesyltransferases. This is because it can be silicided.

[0056] Any substance or any molecule capable of slowing down or inhibiting enzymatically catalyzed farnesylation. The subcomponent may be a farnesyltransferase inhibitor. The slowing of the catalysis rate was similar to that of the reaction without the addition of a farnesyltransferase inhibitor. Farnesyltransferase inhibitor at the site of action at an appropriate concentration compared to the response environment By adding an agent, it is possible to increase the amount of the cellulose in the cellulose membrane by more than 10%, more preferably by more than 25%, and even more preferably by more than 25%. More preferably, it is greater than 50%, even more preferably, it is greater than 75%, even more preferably, it is greater than 50%. More preferably, the ratio is greater than 80%, even more preferably greater than 90%, and most preferably greater than 95%. This can be understood as a deceleration beyond

[0057] More importantly, farnesyltransferase inhibitors inhibit the farnesyltransferase activity of RhoB. As used herein, the term "RhoB" refers to a protein that inhibits cytosylation of RhoB. It has its general meaning in the field of medicine and is encoded in humans by the RHOB gene. The term refers to member B of the ras homolog gene family, a protein that is expressed in the ras subunit.

[0058] In some embodiments, the farnesyltransferase inhibitor is, e.g., farnesyltransferase inhibitor. nesol, farnesyl phosphate, farnesyl diphosphate, or analogs of substrate peptides, etc. The farnesyltransferase inhibitor can be used as an antimetabolite. Different structures capable of binding to the binding pocket of the tide substrate or the farnesyl diphosphate were Alternatively, the farnesyltransferase inhibitor can be a molecule having the formula: It may be an allosteric inhibitor.

[0059] In some embodiments, the farnesyltransferase inhibitor has any molecular structure. For example, this may be a peptidic substance, a peptidomimetic, or a non-peptide Peptide substances can be small molecule substances that consist mostly of peptides. However, peptides can be combined with other molecular structures, such as biologically compatible organic polymers (e.g. For example, polyethylene glycol (PEG), polyethyleneimine (PEI), hydroxy Propyl methacrylamide (HPMA), lipids, alkyl moieties, or other polypeptides Peptide mimetics are compounds whose molecular structure mimics a peptide. Peptide mimetics are substances that mimic the structure of, for example, beta amino acids (single amino acids), gamma amino acids (single amino acids), and The amino acids may be selected from the group consisting of γ-amino acids, D-amino acids, and D-amino acids. A peptide mimetic can be made from a combination of these. The molecular structure can be conjugated to, for example, biologically compatible organic polymers. The peptidomimetic may also be a retro-inverse peptide. The substance should be less than 1500 Da, preferably less than 1000 Da, even more preferably less than 500 Da. A small molecule is a molecule with a molecular weight of less than Da. Small molecules are also molecules that are not part of other molecular structures, e.g. It can be conjugated to a biologically compatible organic polymer.

[0060] In some embodiments, the farnesyltransferase inhibitor is R11577 ( Zarnestra, Tipifarnib), SCH66336( Lonafamib, FTI-277, GGTI-298, BMS -214664, L-778, and L-123.

[0061] In some embodiments, the farnesyltransferase inhibitor of the present invention is typhimurium. As used herein, the term "tipifarnib" refers to Z It is also known by the trade name Arnestra (trademark) (J&JPRD) and is shown below. The FTase inhibitor (R)-6-[amino(4-chlorophenyl)(l- Methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-l- Methyl-2(lH)-quinolinone (also identified as Rl15777). [ka]

[0062] As used herein, the term "combination" refers to the use of a first agent in combination with a further agent. Used to refer to any dosage form provided with a (second, third, etc.) medication. The agents can be administered together, separately or sequentially, and in any order. The administered agent has biological activity in the subject to which it is delivered. Within the context of the invention, a combination comprises at least two different drugs, one of which is less effective than the other. At least one drug is a kinase inhibitor and the other is a farnesyltransferase inhibitor. In some cases, the combinations of the present invention result in synthetic lethality of cancer cells, particularly DTCs. vinegar.

[0063] A "therapeutically effective amount" means an amount effective, at the dosages and for the duration necessary, to achieve a desired therapeutic result. A therapeutically effective amount of a drug is determined based on the individual's medical condition, age, sex, and weight, and the effectiveness of the drug in the individual. The therapeutically effective amount may vary depending on factors such as the ability to elicit a desired response. Any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects. The effective dosage and administration regimen of the drug will depend on the disease or condition to be treated. A physician skilled in the art can determine the effective amount of the pharmaceutical composition required. For example, a physician may determine and prescribe the appropriate dose to achieve a desired therapeutic effect. Initiate the dose of the drug used in the pharmaceutical composition at a level lower than that required for In general, the dosage may be gradually increased until the desired effect is achieved. An appropriate dose of the composition is the lowest effective dose to produce a therapeutic effect with a particular administration regimen. Such an effective dose will generally depend on the factors described above. For example, a therapeutically effective amount for therapeutic use may be sufficient to stabilize disease progression. A therapeutically effective amount of a therapeutic compound can be determined by reducing tumor size in a subject. Such amounts can be determined by those of skill in the art based on the subject's Based on factors such as the size of the subject's body, the severity of the subject's symptoms, and the particular composition or route of administration selected. An exemplary, non-limiting range for a therapeutically effective amount of a drug is from about 0. 1 to 100 mg / kg, for example about 0.1 to 50 mg / kg, for example about 0.1 to 20 mg / kg kg, for example about 0.1 to 10 mg / kg, for example about 0.5, for example about 0.3, about 1, about 3 The therapeutically effective amount of the antibody of the present invention is about 5 mg / kg, about 8 mg / kg, or about 10 mg / kg. Exemplary, non-limiting ranges include 0.02 to 100 mg / kg, for example, about 0.02 to 30 mg. / kg, for example about 0.05 to 10 mg / kg, or 0.1 to 3 mg / kg, for example about 0. The dose is 2 to 5 mg / kg. The administration may be, for example, intravenous, intramuscular, intraperitoneal, or subcutaneous. For example, it can be administered proximal to the target site. Dosage regimens in the present invention may be adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, or several divided doses may be administered over time. or, if indicated by the exigencies of the therapeutic situation, a proportional reduction or increase in the dose may be permitted. In some embodiments, efficacy of treatment may be monitored during therapy, e.g., at predetermined time points. As a non-limiting example, the treatment of the present invention may be performed 1, 2, 3, 4, 5 or 6 days after the start of the treatment. , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 2 0, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 , 34, 35, 36, 37, 38, 39, or 40 days, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 1 1 day for at least one week in weeks 7, 18, 19, or 20, or any combination thereof Approximately 0.1 to 100 mg / kg per unit, e.g., 0.2, 0.5, 0.9, 1.0, 1.1 , 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 1 6, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 , 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg / kg of the present invention. Daily dose of the indicated drug may be administered as a single dose or every 24, 12, 8, 6, 4, or 2 hours. It may be provided using divided doses, or any combination thereof.

[0064] Typically, the agents of the present invention are administered to the subject in the form of a pharmaceutical composition containing a pharma- ceutically acceptable carrier. Pharmaceutically acceptable carriers that can be used in this composition include ion exchange bodies, alumina, aluminum stearate, lecithin, serum proteins, e.g. human serum Albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate a mixture of partial glycerides of vegetable saturated fatty acids, water, salts or electrolytes, e.g., proton sulfate tamin, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colo Silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, poly Ethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax Polyethylene-polyoxypropylene-block polymer, polyethylene glycol For use in administering to a subject, the composition The compositions of the present invention may be formulated for administration to a subject. It can be administered intravenously, topically, rectally, nasally, orally, vaginally, or via an indwelling reservoir. As used herein, the term can refer to subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, This includes intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Sterile injectable forms of the compound may be in the form of an aqueous or oily suspension. These suspensions may be prepared by subjecting the compound to suitable Dispersing or wetting agents and suspending agents are used according to techniques known in the art. Also, a sterile injectable preparation can be formulated, for example, in 1,3-butanediol. As a solution, a sterile injectable solution in a non-toxic parenterally acceptable diluent or solvent or Among the acceptable vehicles and solvents that can be used are water, In addition, sterile fixed oils have traditionally been used as solvents. For this purpose, synthetic mono- or diglycerides are used as solvents or suspending media. Any bland fixed oil may be used, including fatty acids such as oleic acid. and its glyceride derivatives are derived from natural pharma- ceutical acceptable oils such as olive oil or castor oil. Oils, as well as their polyoxyethylated versions, are useful in the preparation of injectables. These oil solutions or suspensions may be diluted with a long-chain alcohol diluent or dispersant, e.g., an emulsion. Carboxymethylcellulose, a carboxymethylcellulose commonly used in the formulation of pharma- ceutical acceptable dosage forms, including suspensions, It may also contain ethyl cellulose or a similar dispersing agent. Other commonly used surfactants, such as an, and pharma- ceutically acceptable solid, liquid, or Other emulsifiers or bioavailability enhancers commonly used in the manufacture of other dosage forms may also be included in the formulation. The composition of the present invention can be used for the purpose of pharmaceutical preparations. The compound may be orally administered in any orally acceptable dosage form, including, but not limited to, a solution. In the case of tablets for oral use, commonly used carriers include lactose, lactic acid bacteria, and lactose. Also included are lubricants such as magnesium stearate. For oral administration in capsule form, useful diluents include, for example, lauroyltransferase. When aqueous suspensions are required for oral use, the active ingredient is added to emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Alternatively, the compositions of the present invention can be administered in the form of suppositories for rectal administration. These allow drugs to be solid at room temperature but liquid at rectal temperature and therefore can be The drug is prepared by mixing the drug with a suitable non-irritating excipient that melts at room temperature and releases the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol. The compositions of the present invention may also be used to treat localized conditions, including disorders of the eye, skin, or lower intestinal tract. When the target of treatment includes an area or organ that is easily accessible by application of Suitable topical formulations can be administered to each of these areas or organs. For topical application, the composition contains the active ingredient suspended or dissolved in one or more carriers. For topical administration of the compounds of the present invention, the compounds can be formulated into a suitable ointment containing The carriers are mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene These include, but are not limited to, polyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the compositions may comprise one or more active ingredients suspended or dissolved in one or more pharma- ceutically acceptable carriers. The composition can be formulated into a suitable lotion or cream containing the ingredient. The body contains mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters water , cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and Topical application for the lower intestinal tract may be effected by rectal suppository (see above), but is not limited to water. This can be done with a suction cup (see below) or with a suitable enema. Alternatively, a patch can be used. The compositions of the present invention may also be administered by nasal aerosol or inhalation. The compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and may include any suitable additives such as benzyl alcohol or glycerol. or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbamides, and / or other conventional solubilizing or dispersing agents in saline. For example, the antibody present in the pharmaceutical composition of the present invention can be prepared by in either 10 g (10 mL) or 500 mg (50 mL) single-use vials The product can be provided in concentrations of 9.0 mg / mL sodium chloride. , 7.35 mg / mL sodium citrate dihydrate, 0.7 mg / mL polysorbate Formulate for intravenous administration in 0.8 mL of 0.8% NaCl and sterile water for injection. The pH is adjusted to 6.5. An exemplary suitable dosage range for the antibody in the pharmaceutical composition of the invention is about 1 mg / m 2 ~ 500 mg / m 2 However, these plans are illustrative and should not be taken as a clinical guide. Consider the affinity and tolerability of the particular antibody in the pharmaceutical composition, which must be determined in the study. It is understood that optimal plans and regimens can be adapted taking into account the The pharmaceutical compositions of the invention for injection (e.g., intramuscular, intravenous) may be prepared in sterile buffered water (e.g., Intramuscularly, 1 ml), about 1 ng to about 100 mg, for example, about 50 ng to about 30 mg or more, preferably Preferably, the composition can be prepared to contain about 5 mg to about 25 mg of the inhibitor of the present invention. .

[0065] A further object of the present invention is to provide a method for the treatment of farnesyltransferase, in particular for use in the treatment of cancer. Pharmaceutical compositions or kits (kits of parts) containing a ferrase inhibitor and a kinase inhibitor do.

[0066] The terms "kit," "product," or "combination preparation" are used herein. As such, the combination partners as defined above may be used individually or in specific amounts of the combination partners. By using various predefined combinations including toners, i.e. together or at various times In particular, the term "parts kit" is defined in the sense that the parts kit can be used for The parts of the kit may be, for example, used together or at different times, i.e., any part of the kit of parts may be used at different times. The parts can be administered at different times and with equal or different time intervals. The ratio of the total amounts of the combination partners administered in a formulation may vary. The administration may be by one or different routes.

[0067] The invention will now be further described by the following figures and examples. The examples and figures should not be construed in any way as limiting the scope of the invention. EXAMPLES

[0068] In vitro RAS-related GTPase RHOB mediates EGFR upregulation following treatment with EGFR-TKIs It has been shown to play a central role in suppressing cell death via the AKT pathway in mutant lung cancer cells. Recently, 18 High RHOB tumor levels suggest that EGFR-TKI-treated EGFR We found that FR-activating mutations predicted early recurrence in NSCLC patients. This was observed in BRAF-mutated melanomas treated with the BRAF inhibitor vemurafenib. Even if 19 The RHOB pathway is a receptor tyrosine kinase that can induce the acquisition of the DTC state. These results suggest that inhibition of the reductase (RTK)-ERK pathway may be a common adaptive mechanism. It shares some characteristics with the known process of treatment-induced senescence (TIS). 20 ,go In vitro drug resistance following EGFR-TKI treatment shows some specific features We therefore identified a new phenotype associated with senility (data not shown). These observations are consistent with the well-described PC9 and All showed initial sensitivity to EGFR-TKIs, but none caused DTC to EGFR-TKIs. HCC827, HCC400, which have not yet been characterized for their potential 6, H3255, and HCC2935 (potential resistant subtypes in the bulk population) A group of EGFR mutant lung cell lines (pre-cloned to ensure no clones existed) Surprisingly, these cell lines All were treated with EGFR-TKI (1 μM erlotinib or osimertinib) several days after Although DTC could be induced in the 100% ... High inter- and intra-cell line variability was observed for several important parameters, including biokinetics For example, PC9, HCC827, and HCC4006 were treated with erlotinib. , which could give rise to proliferation-resistant clones, but HCC2935 and H3225 cells No resistant clones were observed after erlotinib treatment in the line (data available). not shown).

[0069] Despite these differences, a common feature of the DTC state in cell lines is the TI Cell morphology rearrangement upon treatment, with a predominantly flat and expanded morphology consistent with S processes These morphological changes were further investigated and were observed after TKI treatment. We observed a strong increase in actin stress fiber production several days after initiation (data not shown). Actin polymerization is a tightly regulated process governed by GTPases. With knowledge of the role of RHOB in resistance to targeted therapy, this GT We investigated whether Pase could be a cause of stress fiber production in response to EGFR-TKI. First, we assessed whether RHOB protein expression and activity were significantly increased in DTCs of all cell lines. We observed that RHOA and RHOC were strongly inhibited, whereas RHOA and RHOC were significantly increased (data not shown). We also demonstrated that siRNA-specific inhibition of RHOB and C3 exoenzyme (tatC 3) Pharmacological inhibition of RHO-GTPase using α-actin reduces the production of actin stress fibers. Not only did it strongly reduce the IL-1 signaling pathway, it also strongly reduced DTC survival, inhibiting actin remodeling and drug resistance. We found suggestive association with gender (data not shown).

[0070] Although RHOB does not have a specific inhibitor suitable for clinical use, its activity is related to its pre- The methylation state (either farnesylation or geranylgeranylation) determines the Farnesyltransferase inhibitors (FTi) or geranylgeranyltransferase inhibitors Can be targeted by GGTi 21~23 Therefore, multiple In EGFR mutant cell lines (PC9, HCC827, and HCC4006), To determine the efficacy of FTi or GGTi in combination with rotinib in vitro Combination with 1 μM GGTI298 suppressed the emergence of resistant proliferative clones. 1A-1C), whereas the combination of FTi with tipifarnib at 1 μM (Fig. 1A-1C) When used at 0.1 μM (Figure 1C), all drug-resistant cells The results showed that the resistant clones were effectively eliminated and the emergence of resistant clones was sufficiently suppressed. ALK-translocated lung cancer cells (e.g., H3122) treated with tinib (Figure 1G) or Other oncogenic cells, such as BRAF-mutated melanoma cells (A375) treated with phenytoin (Figure 1H) We observed similar results in our model, in which co-treatment with tipifarnib significantly increased the (RTK)-ER These results suggest that this may interfere with other targeted therapies that target the K pathway.

[0071] Tipifarnib used alone at 0.1 μM inhibited the proliferation of PC9 and HCC827 cells. Although it showed little or no effect (data not shown), HCC4006 (data not shown) The data was not shown, and it showed some cell proliferation inhibitory effect on A375 and H3122. This was exacerbated when tipifarnib was used at 1 μM (data not shown). As an example, the combination of tipifarnib (0.1 μM) and erlotinib (1 μM) was The treatment resulted in complete cell death as evidenced by the absence of residual DTCs. Interestingly, NSCLC patients with EGFR mutations The current recommendation of third-generation EGFR-TKIs as standard first-line treatment for patients with The same results were observed with mertinib (data not shown).

[0072] Overall, this in vitro data supports the notion that farnesyltransferase (GlycA) Inhibition of tyrosine (but not ranylgeranyltransferase) is a potential treatment for various carcinogenesis This strongly suggests that the development of resistance to kinase inhibitors can be prevented. On an exciting note, a recently published phase I clinical trial compared erlotinib and tipifarnib. reported that the combination with 24 ,This study E The efficacy of the combination has not been demonstrated in patients with GFR-mutated NSCLC. do not have.

[0073] In vivo Previously described EGFRL858R / T790M lung patient-derived xenograft models (TP103, Pax Ares' lab, CNIO Madrid) at 6-8 weeks of age. The tumors were then subcutaneously implanted into NSG mice (Charles River) and allowed to grow. (average 300-350 mm3) were then administered to the mice. Tipifarnib (n=3), osimertinib (n=6), and osimertinib + tipifarnib Patients were randomly assigned to receive either tipifarnib (n=6) or tipifarnib (n=6) 5 days / week. The patients were administered 80 mg / Kg twice daily by oral gavage, and osimertinib was administered for 5 days / kg. The tumors were administered by oral gavage at 5 mg / Kg once daily for a week. The length and width of the tumor were measured with a vernier caliper, and the tumor volume was calculated as follows: volume = 0.5236 x length The length × width (mm) was calculated, and the mice were weighed once a week. rism (GraphPad software) was used for PFS and OS plots. Unpaired two-tailed t-tests or Mantel-Cox were performed (Figures 2A to 2E).

[0074] References Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are incorporated herein by reference into the present disclosure. 1.Fitzmaurice, C. et al. The Global Bur Den of Cancer 2013. JAMA Oncol 1, 505-52 7, doi:10.1001 / jamaoncol.2015.0735 (2015 ). 2.Rosell, R. et al. Erlotinib versus st andard chemotherapy as first-line treatment ent for European patients with advanced EGFR mutation-positive non-small-cell lu ng cancer (EURTAC): a multicentre, open- label, randomized phase 3 trial. Lancet Oncol 13, 239-246, doi:10.1016 / S1470-204 5(11)70393-X (2012). 3.Engelman, J. A. et al. MET amplificat ion leads to gefitinib resistance in lun g cancer by activating ERBB3 signaling. Science 316, 1039-1043, doi:10.1126 / scie nce.1141478 (2007). 4.Takezawa, K. et al. 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Claims

1. A pharmaceutical composition for treating cancer resistant to a kinase inhibitor, comprising: Contains a farnesyltransferase inhibitor, A pharmaceutical composition administered in combination with a kinase inhibitor.

2. The kinase inhibitors include gefitinib, erlotinib, lapatinib, vandetanib, afatinib, osimertinib, neratinib, dacomitinib, brigutinib, canertinib, nacotinib, nazartinib, pelitinib, rociletinib, icotinib, AZD3759, AZ5104 (CAS number 1421373-98-9), poziotinib, WZ4002, crizotinib, entrectinib, ceritinib, alectinib, lorlatinib, TSR-011, CEP-37440, and ensal. Tinib, vemurafenib, dabrafenib, regorafenib, PLX4720, cobimetinib, trametinib, binimetinib, selumetinib, PD-325901, CI-1040, PD035901, U0126, TAK-733, lenvatinib, Debio-1347, dovitinib, BLU9931, sorafenib, sunitinib, lestaurtinib, tandutinib, quizartinib, crenolanib, gilteritinib, ponatinib, ibrutinib, linsitinib, NVP-AEW54 1, BMS-536924, AG-1024, GSK1838705A, BMS-754807, PQ401, ZD3463, NT157, picropodophyllin (PPP), tivantinib, JNJ-38877605, PF-04217903, foretinib (GSK1363089), merestinib, ruxolitinib, tofacitinib, oclacitinib, baricitinib, filgotinib, cerduratinib, gandotinib, momelotinib, pacritinib, PF-04965842, selected from the group consisting of padacitinib, peficitinib, fedratinib, imatinib, pazopanib, telatinib, bosutinib, nilotinib, cabozantinib, bemcentinib, amuvatinib, gilteritinib (ASP2215), glesatinib (MGCD265), SGI-7079, larotrectinib, RXDX-102, altilatinib, LOXO-195, sitravatinib, TPX-0005, DS-6051b, fostamatinib, entospletinib, and TAK-659; 2. The pharmaceutical composition of claim 1, wherein the farnesyltransferase inhibitor is tipifarnib.

3. The pharmaceutical composition of claim 1 or 2, wherein the cancer is an EGFR-mutated cancer, an ALK-mutated cancer, a RAS-mutated cancer, or a RAF-mutated cancer.

4. 4. The pharmaceutical composition of claim 3, wherein the cancer is selected from the group consisting of leukemia, lymphoma, sarcoma, melanoma, and cancer of the head and neck, kidney, ovary, pancreas, prostate, thyroid, lung, esophagus, breast, bladder, brain, colorectal, liver, and cervix.

5. The pharmaceutical composition of claim 3 , wherein the cancer is non-small cell lung cancer.

6. 4. The method of claim 3, wherein when the kinase inhibitor is an EGFR inhibitor, the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer, pancreatic cancer, breast cancer, particularly early stage breast cancer, thyroid cancer, medullary thyroid cancer, colorectal cancer, metastatic or advanced colorectal cancer, squamous cell carcinoma of the head and neck, and glioma.

7. 4. The method of claim 3, wherein the cancer is non-small cell lung cancer when the kinase inhibitor is an ALK inhibitor.

8. 4. The method of claim 3, wherein when the kinase inhibitor is a B-Raf inhibitor, the cancer is selected from the group consisting of melanoma, lung cancer, colorectal cancer, and gastrointestinal stromal cancer.

9. A pharmaceutical composition or kit (kit of parts) comprising a farnesyltransferase inhibitor and a kinase inhibitor for use in treating cancers resistant to kinase inhibitors.

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