Inhibition of BCL2 family proteins overcomes acquired resistance to standard of care BRAF and MEK inhibitors in a subset of BRAFV600E-mutant melanomas

Anti-apoptotic BCL family proteins have been shown to promote de novo resistance to a number of therapies, including single-agent BRAF inhibitors in BRAF-mutant melanomas. In this study, in vivo testing of a collection of BRAFi- or BRAFi/MEKi treatment-refractory melanoma patient-derived xenograft (PDX) models showed that combining BCL2 inhibitors (BCL2i, navitoclax or venetoclax) with BRAFi and MEKi surprisingly induced potent regressions of a significant subset of these treatment-refractory PDXs.

High basal BCL2 expression correlated with improved sensitivity, while high basal MCL1 predicted resistance to BCL2i combination with BRAFi/MEKi. Studies with MCL1 overexpression functionally validated its role in resistance. Further, combination of BRAFi/MEKi with a MCL1 inhibitor (MCL1i) counteracted the resistance and also decreased MCL1i-associated cardiotoxicity markers.