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Figure S4 from Inhibition of BCL2 Family Members Increases the Efficacy of Copper Chelation in BRAFV600E-Driven Melanoma

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posted on 2023-12-22, 18:20 authored by Ye-Jin Kim, Tiffany Tsang, Grace R. Anderson, Jessica M. Posimo, Donita C. Brady

Supplemental Figure S4. Targeting select BCL2 family proteins increases sensitivity to TTM in BRAFV600E-positive melanoma.

Funding

Pew Charitable Trust

Tara Miller Foundation

Wistar Institute

NCI

American Cancer Society

History

ARTICLE ABSTRACT

The principal unmet need in BRAFV600E-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 BRAFV600E-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 BRAFV600E-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 BRAFV600E-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 BRAFV600E-driven melanoma. This study unveils a novel collateral drug sensitivity elicited by combining copper chelators and BH3 mimetics for treatment of BRAFV600E mutation-positive melanoma.

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    Cancer Research

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    Keywords

    Cell Death And Senescencebcl-2 pathwaysCell SignalingProtein serine-threonine kinasesDrug Discovery TechnologiesScreening strategies (assays and chemical libraries)Drug MechanismsDrug-mediated stimulation of cell death pathwaysDrug TargetsProtein kinase & phosphatase drug targetsPharmacologyMolecular pharmacologySkin CancersMelanomaSmall Molecule AgentsKinase inhibitors

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