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.
Authors
- Evelyn de Groot (ORCID: https://orcid.org/0000-0002-0330-6246)
- Courtney W. Hudgens (ORCID: https://orcid.org/0000-0001-8312-7485)
- Ryan J. Sullivan (ORCID: https://orcid.org/0000-0001-5344-6645)
- Phyu P. Aung (ORCID: https://orcid.org/0000-0002-3398-0573)
- J. Roszik
- Meenhard Herlyn (ORCID: https://orcid.org/0000-0003-0839-0739)
- Gregory Fontenot
- Debora Alejandra Ledesma (ORCID: https://orcid.org/0000-0002-6670-7645)
- Lawrence N. Kwong (ORCID: https://orcid.org/0000-0001-8370-1432)
- Michael A. Davies (ORCID: https://orcid.org/0000-0002-0977-0912)
- Rehan Akbani (ORCID: https://orcid.org/0000-0003-2686-7721)
- Toshitha Kannan (ORCID: https://orcid.org/0009-0007-7775-6585)
- Clifford Stephan (ORCID: https://orcid.org/0000-0003-0657-6484)
- Michael S. Nakazawa (ORCID: https://orcid.org/0000-0002-6272-5467)
- Y.N. Vashisht Gopal (ORCID: https://orcid.org/0000-0002-3118-0011)
- Vito W. Rebecca (ORCID: https://orcid.org/0000-0001-8124-0900)
- Zhenlin Ju (ORCID: https://orcid.org/0000-0001-7496-7909)
- Monzy Thomas
- Mudassar Ali (ORCID: https://orcid.org/0009-0009-4526-8389)
- Andrew Kossenkov
- Diana Shamsutdinova
- Khalida Wani (ORCID: https://orcid.org/0000-0002-2383-3908)
- Min Xiao
- Barbara Knighton
- Kaley Loftin
Institutions
- The Wistar Institute (US)
- The University of Texas MD Anderson Cancer Center (US)
- Johns Hopkins University (US)
- Baylor College of Medicine (US)
- Dana-Farber Cancer Institute (US)
- The University of Texas Medical Branch at Galveston (US)
- Texas A&M University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-06-26
- DOI
- https://doi.org/10.1038/s41467-026-74691-9
- Primary Topic
- Melanoma and MAPK Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Cancer Prevention and Research Institute of Texas
- Melanoma Research Alliance
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- AIM at Melanoma
- China National Center for Food Safety Risk Assessment
- National Institutes of Health
- University of Texas MD Anderson Cancer Center
- National Cancer Institute