Personalized targeting of BCL2 family proteins overcomes acquired resistance to BRAF-MEK inhibitors in preclinical melanoma
- Vashisht Gopal Y.N
- Evelyn de Groot
- Kaley Loftin
- Barbara Knighton
- Debora Ledesma
- Courtney Hudgens
- Diana Shamsutdinova
- Mehboob Ali
- Zhenlin Ju
- Min Xiao
- Toshitha Kannan
- Gregory Fontenot
- Michael S. Nakazawa
- Monzy Thomas
- Khalida Wani
- Clifford Stephan
- Phyu P. Aung
- Lawrence N. Kwong
- Janos Roszik
- Rehan Akbani
- Andrew Kossenkov
- Vito W. Rebecca
- Ryan J. Sullivan
- Meenhard Herlyn
- Michael A. Davies
2026-06-26
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.