Inhibition of BCL2 Family Members Increases the Efficacy of Copper Chelation in BRAF^V600E-Driven Melanoma.

ABSTRACT: The principal unmet need in BRAF^V600E-positive melanoma is lack of an adequate therapeutic strategy capable of overcoming resistance to clinically approved targeted therapies against oncogenic BRAF and/or the downstream MEK1/2 kinases. We previously discovered that copper (Cu) is required for MEK1 and MEK2 activity through a direct Cu-MEK1/2 interaction. Repurposing the clinical Cu chelator tetrathiomolybdate (TTM) is supported by efficacy in BRAF^V600E-driven melanoma models, due in part to inhibition of MEK1/2 kinase activity. However, the antineoplastic activity of Cu chelators is cytostatic. Here, we performed high-throughput small-molecule screens to identify bioactive compounds that synergize with TTM in BRAF^V600E-driven melanoma cells. Genetic perturb

SUBMITTER: Kim YJ 

PROVIDER: S-EPMC7127963 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature