DDX43 AS A BIOMARKER OF RESISTANCE TO MEK1/2 INHIBITORS

摘要

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.

主权项

1. A method of 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 contain an increased level of DDX43 mRNA and/or DDX43 protein, where if the level of DDX43 mRNA and/or protein is increased, it is unlikely that a MEK inhibitor would have an anti-cancer effect on the cancer.