A new study led by researchers at the University of Texas MD Anderson Cancer Center has identified a way to tailor drug combinations based on specific tumor biology to improve outcomes in treatment-resistant, advanced melanoma.
In preclinical models of patients with treatment-resistant tumors, combining standard BRAF and MEK inhibitors with drugs that block BCL2 family proteins that promote tumor growth induced tumor regression in a molecularly defined subset of resistant tumors, suggesting a path toward biomarker-based therapy.
This study nature communicationsThe study was led by Vashisht Gopal Yenu Nanda, PhD, associate professor of melanoma medical oncology and translational molecular pathology, in collaboration with senior author Michael A. Davis, MD, chair of melanoma medical oncology.
“Targeted therapies work by blocking the main signals that drive melanoma growth, but tumors often have backup systems that keep them alive,” said Yenu Nanda. “By identifying which proteins tumors rely on for survival, we may be able to match patients with drug combinations tailored to their specific tumor biology.”
Why are certain melanomas resistant to treatment?
About half of all melanomas have mutations in the BRAF gene, which causes uncontrolled tumor growth. For nearly a decade, the standard treatment for these patients has been a combination of BRAF and MEK inhibitors, which was initially effective for most patients. However, approximately 80% of patients develop resistance and disease progression within two years. This may be due to an increase in specific proteins within the BCL2 family.
Cancer cells often evade treatment by increasing their production of “survival proteins” from the BCL2 family (usually BCL2, BCL-xL, and MCL1). The researchers found that melanoma tumors expressed unusually high levels of these proteins compared to most other cancer types, and that BCL2 levels were increased in patients after BRAF-MEK inhibitor therapy, likely contributing to treatment resistance.
How does blocking these “survival proteins” cause tumors to shrink? And how do doctors know which proteins to target?
Researchers tested the addition of a BCL2 inhibitor (navitoclax or venetoclax) to a standard two-drug regimen using a large collection of patient-derived xenograft (PDX) models established from melanomas that had acquired resistance to standard treatments. They found that with the new combination of these models, a subset of tumors that were previously resistant now regress.
Tumors with high baseline levels of BCL2 tended to respond, whereas tumors with high baseline MCL1 expression tended to resist. To confirm the role of MCL1, the researchers artificially increased MCL1 levels in tumor cells and induced resistance to the triple combination.
For tumors that overproduce MCL1, the researchers tested an alternative therapy by combining a BRAF-MEK inhibitor with an experimental MCL1 inhibitor called AZD5991. In the high-MCL1 PDX model, this combination resulted in complete tumor regression and no detectable tumors at the end of the experiment.
What is hindering the progress of MCL1 inhibitors in clinical practice?
MCL1 inhibitors have previously shown antitumor activity, but early clinical trials linked them to heart-related side effects, causing some studies to be paused or discontinued. In this study, the addition of a BRAF-MEK inhibitor appears to protect cardiac cells from the damaging effects of an MCL1 inhibitor.
In laboratory models, only MCL1 inhibitors interfered with energy production in heart cells and caused signs of damage. Addition of BRAF and MEK inhibitors significantly reversed these effects. This may be because the MEK inhibitor helped restore energy production in heart cells, which is inhibited by the MCL1 inhibitor. Further research is needed to determine whether this protective effect is transmitted to patients.
“We did not expect that combining these drugs would reduce the toxicity of MCL1 inhibitors,” Davis said. “If confirmed in clinical trials, this finding could give a second life to certain drugs that have struggled to make progress in development. It also confirms that the most effective combinations are those that eliminate cancer while sparing healthy tissue.”
What are the next steps for this research?
These findings support the design of biomarker-based clinical trials that match patient and drug combinations based on tumor BCL2 and MCL1 expression. To further this research, the team is analyzing samples from a recent randomized phase 2 clinical trial of dabrafenib, trametinib, and navitoclax in patients with BRAF-mutant melanoma to determine whether MCL1 expression predicts clinical response. Additional preclinical and translational studies are needed to assess the safety of the combination of BRAF-MEK and MCL1 inhibitors before they can be evaluated in patients.
“Patients whose melanoma no longer responds to standard treatments currently have few effective treatment options,” said Dr. Yenu Nanda. “Our findings may help address this critical need in these patients by guiding clinicians to tailor combinations to each individual’s tumor.”
sauce:
University of Texas MD Anderson Cancer Center
Reference magazines:
Vashisht Gopal, YN, Others. (2026) Personalized targeting of BCL2 family proteins overcomes acquired resistance to BRAF-MEK inhibitors in preclinical melanoma. nature communications. DOI: 10.1038/s41467-026-74691-9. https://www.nature.com/articles/s41467-026-74691-9
