Copper Chelation Inhibits BRAFV600E-Driven Melanomagenesis and Counters Resistance to BRAFV600E and MEK1/2 Inhibitors

Abstract

MEK1/2 and BRAF^V600E inhibitors are used to treat BRAF^V600E-positive melanoma, with other cancers under evaluation. Genetic perturbation of copper import or pharmacologic reduction of copper with the clinical copper chelator TTM inhibits MEK1/2 kinase activity and reduces BRAF^V600E-driven tumorigenesis. In this study, we report that TTM inhibited transformed growth of melanoma cell lines resistant to BRAF or MEK1/2 inhibitors and enhanced the antineoplastic activity of these inhibitors. TTM also provided a survival advantage in a genetically engineered mouse model of melanoma, and when accounting for putative overdosing, trended toward an increase in the survival benefit afforded by BRAF inhibition. This effect was phenocopied by genetically inhibiting copper import in tumors, which was linked to a reduction in MAPK signaling. Thus, TTM reduces copper levels and MAPK signaling, thereby inhibiting BRAF^V600E-driven melanoma tumor growth. These observations inform and support clinical evaluation of TTM in melanoma. <i>Cancer Res; 77(22); 6240-52. ©2017 AACR</i>.