DDX43 as a biomarker of resistance to MEK1/2 inhibitors
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.
1. A method of treating a subject having a uveal melanoma 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 contain an increased level of DDX43 mRNA and/or DDX43 protein relative to a normal value or normal values; and (ii) treating the subject with a therapeutic amount of a MEK inhibitor if the level of DDX43 mRNA and/or protein is not increased or (iii) treating the subject with a therapeutic amount of an AKT inhibitor where the level of DDX43 mRNA and/or protein is increased.
2. The method of claim 1 , wherein the AKT inhibitor is selected from the group consisting of VQD-002, perifosine, miltefosine, AZD5363, and MK2206.
3. The method of claim 2 , wherein the AKT inhibitor is MK2206.
4. 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.
5. The method of claim 4 , wherein the MEK inhibitor is selumetinib.
6. The method of claim 1 , wherein (iii) further comprises treating the subject with a therapeutic amount of an AKT inhibitor where the level of DDX43 mRNA and/or protein is increased by at least a factor of about 10, at least a factor of about 15, at least a factor of about 20, at least a factor of about 30, at least a factor of about 40, or at least a factor of about 50, relative to the normal value or normal values.