# US 11,078,540 B2 · Methods of diagnosing and treating cancer in patients having or developing resistance to a first cancer therapy > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,078,540 B2 - Document ID: US11078540B2 - Status: Granted - Kind: B2 - Application number: 15/480,126 - Filed: 2017-04-05 - Published: 2017-09-21 - Granted: 2021-08-03 - Earliest claimed: 2010-03-09 - Assignees: Dana-Farber Cancer Institute, Inc.; The Broad Institute, Inc. - Applicants: Levi A. Garraway; Cory M. Johannessen - Inventors: Levi A. Garraway; Cory M. Johannessen - Web page: https://patentgrep.com/patent/US11078540B2 ## CPC - C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575) - A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles - A61P 35/00: Antineoplastic agents - A61P 35/02: specific for leukemia - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C12N 9/12: transferring phosphorus containing groups, e.g. kinases (2.7) - C12N 9/1205: {Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases} - C12Y 207/11024: Mitogen-activated protein kinase (2.7.11.24), i.e. MAPK or MAPK2 or c-Jun N-terminal kinase - C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism - C12Q 2600/158: Expression markers - C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) - C12Y: ENZYMES ## Abstract A method of identifying a subject having cancer who is likely to benefit from treatment with a combination therapy with a RAF inhibitor and a second inhibitor is provided. A method of treating cancer in a subject in need thereof is also provided and includes administering to the subject an effective amount of a RAF inhibitor and an effective amount of a second inhibitor, wherein the second inhibitor is a MEK inhibitor, a CRAF inhibitor, a CrkL inhibitor or a TPL2/COT inhibitor. A method of identifying a kinase target that confers resistance to a first inhibitor is also provided. ## Claims ### Claim 1 A method of treating cancer in a first subject in need thereof, comprising administering to the first subject an effective amount of a RAF inhibitor selected from the group consisting of RAF265, sorafenib, SB590885, PLX 4720, PLX4032, GDC-0879 and ZM 336372, and an effective amount of a second inhibitor, wherein the second inhibitor is a MAP3K8 (TPL2/COT) inhibitor selected from the group consisting of 4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-ylmethylamino)-3-cyano-[1,7]-naphthyridine, the inhibitory RNA of SEQ ID NO: 16, and the inhibitory RNA of SEQ ID NO: 17. ### Claim 2 (depends on 1) The method of claim 1, wherein the cancer in the first subject has cancer cells comprising a BRAF mutation or a B-RAFV600E mutation. ### Claim 3 (depends on 2) The method of claim 2, wherein the cancer in the first subject has cancer cells comprising a B-RAFV600E mutation. ### Claim 4 (depends on 1) The method of claim 1, further comprising assaying a gene copy number, a mRNA or a protein level or phosphorylation of one or more kinase targets selected from the group consisting of MAP3K8 (TPL2/COT), RAF1 (CRAF), CRKL(CrkL), FGR (Fgr), PRKCE (Prkce), PRKCH (Prkch), ERBB2 (ErbB2), AXL (Axl), and PAK3 (Pak3) in cancer cells obtained from the first subject and comparing the gene copy number, the mRNA or the protein level or the phosphorylation with a gene copy number, a mRNA or a protein level or phosphorylation of the target kinase in cells obtained from a second subject without the cancer; and administering the effective amount of the RAF inhibitor and the effective amount of the second inhibitor to the first subject having an increased gene copy number or an alteration in mRNA expression or protein overexpression or phosphorylation of the target kinase in the cancer cells obtained from the first subject relative to the cells obtained from a second subject without the cancer. ### Claim 5 (depends on 1) The method of claim 1, wherein the first subject has innate resistance to the RAF inhibitor. ### Claim 6 (depends on 1) The method of claim 1, wherein the cancer is selected from the group consisting of melanoma, breast cancer, colorectal cancers, glioma, lung cancer, ovarian cancer, sarcoma and thyroid cancer. ### Claim 7 (depends on 1) The method of claim 1, wherein the cancer is melanoma. ### Claim 8 A method of treating cancer in a first subject in need thereof, the method comprising: identifying a first subject having an increased gene copy number or an alteration in mRNA expression or protein overexpression or phosphorylation of one or more kinase targets in cancer cells of the first subject relative to cells of a second subject without the cancer, the one or more kinase targets selected from the group consisting of MAP3K8 (TPL2/COT), CRKL(CrkL), FGR (Fgr), PRKCE (Prkce), PRKCH (Prkch), ERBB2 (ErbB2), AXL (Axl), and PAK3 (Pak3); and administering to the first subject an effective amount of a RAF inhibitor selected from the group consisting of RAF265, sorafenib, SB590885, PLX 4720, PLX4032, GDC-0879 and ZM 336372, and an effective amount of a second inhibitor, wherein the second inhibitor is a MAP3K8 (TPL2/COT) inhibitor selected from the group consisting of 4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-ylmethylamino)-3-cyano-[1,7]-naphthyridine, the inhibitory RNA of SEQ ID NO: 16, and the inhibitory RNA of SEQ ID NO: 17. ### Claim 9 (depends on 8) The method of claim 8, wherein the subject has innate resistance to the RAF inhibitor. ### Claim 10 (depends on 8) The method of claim 8, wherein the cancer is selected from the group consisting of melanoma, breast cancer, colorectal cancers, glioma, lung cancer, ovarian cancer, sarcoma and thyroid cancer. ### Claim 11 (depends on 8) The method of claim 8, wherein the cancer is melanoma. ### Claim 12 (depends on 8) The method of claim 8, wherein the first subject has cancer cells comprising a B-RAFV600E mutation.