期刊
CANCER RESEARCH
卷 80, 期 7, 页码 1387-1400出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-19-1784
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资金
- Pew Charitable Trust Pew Scholars Program in Biomedical Science Award [50359]
- Tara Miller Foundation at University of Pennsylvania/Wistar Institute - Skin Cancer SPORE Career Enhancement Program Award [P50CA174523]
- NCI NRSA Fellowship (F31) [F31CA243294]
- NCI [K00CA222728]
- American Cancer Society Postdoctoral Fellowship [131203PF1714701CCG]
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 perturbation or pharmacologic inhibition of specific members of the BCL2 family of antiapoptotic proteins (BCL-W, BCL-XL, and MCL1) selectively reduced cell viability when combined with a Cu chelator and induced CASPASE-dependent cell death. Further, in BRAF(V600E)-positive melanoma cells evolved to be resistant to BRAF and/or MEK1/2 inhibitors, combined treatment with TTM and the clinically evaluated BCL2 inhibitor, ABT-263, restored tumor growth suppression and induced apoptosis. These findings further support Cu chelation as a therapeutic strategy to target oncogene-dependent tumor cell growth and survival by enhancing Cu chelator efficacy with chemical inducers of apoptosis, especially in the context of refractory or relapsed BRAF(V600E)-driven melanoma. Significance: This study unveils a novel collateral drug sensitivity elicited by combining copper chelators and BH3 mimetics for treatment of BRAF(V600E) mutation-positive melanoma.
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