# US 2019/0376149 A1 · Ddx43 as a biomarker of resistance to mek1/2 inhibitors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2019/0376149 A1 - Document ID: US20190376149A1 - Status: Published application - Kind: A1 - Application number: 16/520,078 - Filed: 2019-07-23 - Published: 2019-12-12 - Earliest claimed: 2013-09-05 - Assignees: Memorial Sloan Kettering Cancer Center - Applicants: Memorial Sloan-Kettering Cancer Center - Inventors: Grazia Ambrosini; Raya Khanin; Richard Carvajal; Gary K. Schwartz - Web page: https://patentgrep.com/patent/US20190376149A1 ## CPC - C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575) - A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles - A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine - G01N 33/5751: of the skin, e.g. melanoma - C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism - C12Q 2600/136: Screening for pharmacological compounds - C12Q 2600/158: Expression markers - G01N 2333/914: Hydrolases (3) - 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) - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) ## Abstract The present invention relates to methods and compositions for determining the likelihood that a subject suffering from a cancer will benefit from treatment with a MEK inhibitor. It also relates to methods of treatment based on such determination. The invention is based, at least in part, on the discoveries that DDX43 mRNA and protein are expressed at high levels in biopsies from “non-responder” UM patients and that selumetinib-resistant cell lines showed high DDX43 expression which correlated with increased expression and activity of RAS. It was found that KRAS and HRAS but not NRAS, mediated expression of pERK and pAKT, bypassing oncogenic GNAQ. The invention is further based on the discovery that selumetinib-resistant cells became sensitive to AKT inhibition, suggesting alternative strategies for the treatment of cancer patients with acquired resistance to MEK inhibitors. ## Claims ### Claim 1 A method of treating a subject having a cancer, comprising: (i) determining whether an anti-cancer effect is unlikely to be produced in a cancer by a MEK inhibitor, comprising determining whether cells of the cancer comprise an increased level of mRNA and/or protein corresponding to an exon of one or more of MFAPS, DPYS, ACCN4, and DMKN relative to a normal value or normal values; and (ii) treating the subject with a MEK inhibitor if the level of mRNA and/or protein corresponding to an exon of one or more of RHBG, MFAPS, DPYS, ACCN4, and DMKN is not increased, or (iii) treating the subject with an anti-cancer agent other than a MEK inhibitor if the level of mRNA and/or protein corresponding to an exon of one or more RHBG, MFAPS, DPYS, ACCN4, and DMKN is increased. ### Claim 2 (depends on 1) The method of claim 1, wherein the cancer is melanoma. ### Claim 3 (depends on 1) The method of claim 1, wherein the cancer is melanoma comprises one or more mutations in GNAQ and/or GNA11. ### Claim 4 (depends on 1) The method of claim 1, wherein the cancer is uveal melanoma. ### Claim 5 (depends on 1) The method of claim 1, wherein the anti-cancer agent other than a MEK inhibitor is an AKT inhibitor. ### Claim 6 (depends on 5) The method of claim 5, wherein the AKT inhibitor is selected from the group consisting of VQD-002, perifosine, miltefosine, AZD5363, and MK2206. ### Claim 7 (depends on 6) The method of claim 6, wherein the AKT inhibitor is MK2206. ### Claim 8 (depends on 1) The method of claim 1, wherein the MEK inhibitor is selected from the group consisting of selumetinib, trametinib, MEK162, PD-325901, XL518, and CI-1040. ### Claim 9 (depends on 8) The method of claim 8, wherein the MEK inhibitor is selumetinib. ### Claim 10 (depends on 1) The method of claim 1, wherein (i) further comprises determining whether the cells of the cancer comprise an increased level of DDX43 mRNA and/or DDX43 protein relative to a normal value or normal values. ### Claim 11 (depends on 10) The method of claim 10, wherein the level of DDX43 mRNA and/or protein in the cells of the subject treated in (ii) is not increased. ### Claim 12 (depends on 10) The method of claim 10, wherein the level of DDX43 mRNA and/or protein in the cells of the subject treated in (iii) is increased. ### Claim 13 A method of treating a subject having a cancer comprising: (i) determining whether an anti-cancer effect is unlikely to be produced in the cancer by a MEK inhibitor, comprising determining whether cells of the cancer comprise an increased level of mRNA or protein corresponding to one or more genes or exons listed in Table 1 relative to a normal value or values, and (ii) treating the subject with a MEK inhibitor if the level of mRNA or protein corresponding to one or more gene or exon listed in Table 1 is not increased; or (iii) treating the subject with an anti-cancer agent other than a MEK inhibitor if the level of mRNA or protein corresponding to one or more gene or exon listed in Table 1 is increased. ### Claim 14 (depends on 13) The method of claim 13, wherein the cancer is melanoma. ### Claim 15 (depends on 13) The method of claim 13, wherein the cancer is melanoma comprises one or more mutations in GNAQ and/or GNA11. ### Claim 16 (depends on 13) The method of claim 13, wherein the anti-cancer agent other than a MEK inhibitor is an AKT inhibitor. ### Claim 17 (depends on 13) The method of claim 13, wherein the MEK inhibitor is selected from the group consisting of selumetinib, trametinib, MEK162, PD-325901, XL518, and CI-1040. ### Claim 18 (depends on 13) The method of claim 13, wherein (i) further comprises determining whether the cells of the cancer comprise an increased level of DDX43 mRNA and/or DDX43 protein relative to a normal value or normal values. ### Claim 19 (depends on 18) The method of claim 18, wherein the level of DDX43 mRNA and/or protein in the cells of the subject treated in (ii) is not increased. ### Claim 20 (depends on 18) The method of claim 18, wherein the level of DDX43 mRNA and/or protein in the cells of the subject treated in (iii) is increased.