Ddx43 as a biomarker of resistance to mek1/2 inhibitors

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.

What is claimed is: 
     
         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.   
     
     
         2 . The method of  claim 1 , wherein the cancer is melanoma. 
     
     
         3 . The method of  claim 1 , wherein the cancer is melanoma comprises one or more mutations in GNAQ and/or GNA11. 
     
     
         4 . The method of  claim 1 , wherein the cancer is uveal melanoma. 
     
     
         5 . The method of  claim 1 , wherein the anti-cancer agent other than a MEK inhibitor is an AKT inhibitor. 
     
     
         6 . The method of  claim 5 , wherein the AKT inhibitor is selected from the group consisting of VQD-002, perifosine, miltefosine, AZD5363, and MK2206. 
     
     
         7 . The method of  claim 6 , wherein the AKT inhibitor is MK2206. 
     
     
         8 . 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. 
     
     
         9 . The method of  claim 8 , wherein the MEK inhibitor is selumetinib. 
     
     
         10 . 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. 
     
     
         11 . 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. 
     
     
         12 . 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. 
     
     
         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.   
     
     
         14 . The method of  claim 13 , wherein the cancer is melanoma. 
     
     
         15 . The method of  claim 13 , wherein the cancer is melanoma comprises one or more mutations in GNAQ and/or GNA11. 
     
     
         16 . The method of  claim 13 , wherein the anti-cancer agent other than a MEK inhibitor is an AKT inhibitor. 
     
     
         17 . 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. 
     
     
         18 . 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. 
     
     
         19 . 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. 
     
     
         20 . 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.