00085472can191784-sup-223624_2_supp_6032383_q4n9lb.pdf (1.57 MB)
Figure S3 from Inhibition of BCL2 Family Members Increases the Efficacy of Copper Chelation in BRAFV600E-Driven Melanoma
journal contribution
posted on 2023-12-22, 18:20 authored by Ye-Jin Kim, Tiffany Tsang, Grace R. Anderson, Jessica M. Posimo, Donita C. BradySupplemental Figure S3. Normalized percent inhibition of bioactive compound library alone or in combination with IC20 of TTM in BRAFV600E-positive melanoma cells.
Funding
Pew Charitable Trust
Tara Miller Foundation
Wistar Institute
NCI
American Cancer Society
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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.Usage metrics
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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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