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 for advanced, treatment-resistant melanoma.
In preclinical models from patients with treatment-resistant tumors, combining standard BRAF and MEK inhibitors with a drug to block BCL2 family proteins—which drive tumor growth—caused tumor regression in a molecularly defined subset of resistant tumors, indicating a path toward biomarker-guided therapy.
The study, published in Nature communicationsled by Vashisht Gopal Yennu Nanda, Ph.D., associate professor of Melanoma Medical Oncology and Translational Molecular Pathology, in collaboration with senior author Michael A. Davies, MD, Ph.D., chair of Melanoma Medical Oncology.
“Targeted therapy works by shutting down the main signal that drives melanoma growth, but tumors often have backup systems that keep them alive,” Yennu Nanda said. “By identifying which protein a tumor relies on for survival, we may be able to match patients with drug combinations tailored to their specific tumor biology.”
Why do some melanomas become resistant to treatment?
About half of all melanomas carry a mutation in the BRAF gene, which leads to uncontrolled tumor growth. For nearly a decade, the standard of care for these patients has been a combination of BRAF and MEK inhibitors, which initially works for most patients. However, about 80% of patients develop acquired resistance and disease progression within two years, possibly due to an increase in certain proteins in the BCL2 family.
Cancer cells often evade treatment by increasing production of ‘survival proteins’ in the BCL2 family – usually BCL2, BCL-xL and MCL1. The researchers confirmed that melanoma tumors express unusually high levels of these proteins compared to most other types of cancer, and that BCL2 levels are increased in patients on BRAF-MEK inhibitor treatments, likely contributing to treatment resistance.
How does blocking these “survival proteins” shrink tumors, and how can doctors know which protein to target?
Using a large collection of patient-derived xenograft (PDX) models generated from melanomas with acquired resistance to standard therapy, the researchers tested the addition of a BCL2 inhibitor (navitoclax or venetoclax) to the standard two-drug regimen. They found a subset of previously resistant tumors that now regressed with the new combination in these models.
Tumors with high baseline BCL2 levels tended to respond, while tumors with high baseline MCL1 expression tended to be resistant. To confirm the role of MCL1, the researchers artificially increased its levels in cancer cells, which caused resistance to the triple combination.
For tumors that overproduce MCL1, the team tested an alternative regimen by pairing BRAF-MEK inhibitors with an experimental MCL1 inhibitor called AZD5991. In a high MCL1 PDX model, this combination produced complete tumor regression, with no detectable tumors at the end of the experiment.
What has prevented MCL1 inhibitors from advancing into clinical practice?
MCL1 inhibitors have previously shown anticancer activity, but have been associated with heart-related side effects in early clinical trials, causing several studies to be suspended or stopped. In this study, the addition of BRAF-MEK inhibitors appeared to protect cardiac cells from the damaging effects of the MCL1 inhibitor.
In lab models, the MCL1 inhibitor alone stopped heart cells from producing energy and caused signs of damage. The addition of BRAF and MEK inhibitors largely reversed these effects, possibly because the MEK inhibitor helped restore energy production in the heart cells that the MCL1 inhibitors otherwise disrupt. Further research is needed to determine whether this protective effect translates to patients.
“We did not expect that the combination of these drugs would reduce the toxicity of the MCL1 inhibitor,” Davies said. “If this finding is confirmed in clinical trials, it could give a second lease of life to a class of drugs that has struggled to move through development. It also reinforces that the most effective combinations are those that eliminate cancer while sparing healthy tissue.”
What’s next for this research?
These findings support the design of biomarker-guided clinical trials that match patients to drug combinations based on BCL2 and MCL1 tumor 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-mutated melanoma to determine whether MCL1 expression predicted clinical response. Additional preclinical and translational studies will be needed to evaluate the safety of BRAF-MEK inhibitor and MCL1 inhibitor combinations before they can be evaluated in patients.
“Patients whose melanoma has stopped responding to standard therapies currently have very few effective treatment options,” said Yennu Nanda. “Our findings could help address this critical need for these patients, guiding clinicians to combinations tailored to each individual’s tumors.”
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