Personalized targeting of BCL2 family proteins overcomes acquired resistance to BRAF-MEK inhibitors in preclinical melanoma

Cancer research · Melanoma · BRAF

Personalized targeting of BCL2 family proteins overcomes acquired resistance to BRAF-MEK inhibitors in preclinical melanoma

There are currently no effective targeted therapies for BRAF‑mutant metastatic melanoma patients with acquired resistance to approved BRAF and MEK inhibitors (BRAFi and MEKi), and very few ongoing clinical trials. Anti‑apoptotic BCL2 family proteins promote de novo resistance to several therapies, including single‑agent BRAFi in BRAF‑mutant melanomas. In this study, in vivo testing of a large collection of patient‑derived xenograft (PDX) models from melanoma patients with acquired resistance to BRAFi or BRAFi+MEKi shows that combining BCL2 inhibitors (BCL2i; navitoclax or venetoclax) with BRAFi+MEKi induces tumor regressions in a subset of these PDXs. High basal BCL2 predicts response whereas high basal MCL1 predicts resistance to this strategy. MCL1 overexpression studies functionally validate its role in resistance. Further, combining BRAFi+MEKi with an MCL1 inhibitor (MCL1i) counteracts resistance and interestingly decreases MCL1i‑associated markers of cardiotoxicity. Together these studies identify potential personalized strategies to improve outcomes in this challenging patient population.

This study demonstrates that combining BCL2 family inhibitors with existing BRAF/MEK therapies can overcome resistance in melanoma, suggesting a personalized therapeutic strategy for patients who have progressed on standard targeted treatments.

Evidence level: Sejtvonalas. Laboratóriumi sejtekben vizsgálták.

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