Targeting BCL2 family proteins may counteract acquired resistance to BRAF and MEK inhibition in patients with BRAF-mutant metastatic melanoma, according to findings from a preclinical study published in Nature Communications.
“Targeted therapy works by shutting down the main signal driving melanoma growth, but tumors often have backup systems that keep them alive,” said lead study author Vashisht Gopal Yennu Nanda, PhD, Associate Professor of Melanoma Medical Oncology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center. “By identifying which protein a tumor relies on for survival, we may be able to match patients to drug combinations tailored to their specific tumor biology.”
Background and Study Methods
Researchers considered the targeting of anti-apoptotic BCL2 family proteins, which promote de novo resistance to therapy, as a means to overcome acquired resistance in BRAF-mutant metastatic melanoma.
They conducted in vivo testing of patient-derived xenograft models from patients with melanoma who had acquired resistance to BRAF inhibition monotherapy or combination BRAF and MEK inhibition.
Key Findings
Use of BCL2 inhibition with navitoclax or venetoclax in combination with BRAF and MEK inhibition reduced tumor volume in a subset of the xenograft models.
A high basal BCL2 level predicted response to the triplet regimen, but a high basal MCL1 level predicted resistance. Studies of MCL1 overexpression validated the role of MCL1 in resisting treatment.
The combination of BRAF and MEK inhibition plus an MCL1 inhibitor overcame acquired resistance and decreased markers of MCL1 inhibition–associated cardiotoxicity.
“We did not anticipate that pairing these drugs would reduce MCL1 inhibitor toxicity,” said senior author Michael A. Davies, MD, PhD, the Chair of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center. “If this finding is confirmed in clinical trials, it could give a second life to a class of drugs that has struggled to advance through development. It also reinforces that the most effective combinations are those that eliminate cancer while sparing healthy tissue.”
“Patients whose melanoma has stopped responding to standard therapies currently have very few effective treatment options,” Dr. Yennu Nanda said. “Our findings could help address this critical need for these patients by guiding clinicians toward combinations tailored to each individual’s tumors.”
DISCLOSURES: This research was supported by the National Cancer Institute, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation, the American Cancer Society, the Melanoma Research Alliance, Cancer Fighters of Houston, the Anne and John Mendelsohn Chair for Cancer Research, the Cancer Prevention and Research Institute of Texas (CPRIT), and philanthropic contributions to UT MD Anderson. For full disclosures of the study authors, visit nature.com.
