Biomarker-guided drug combinations may improve outcomes in treatment-resistant melanoma

UT MD Anderson Research News July 02, 2026

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 treatment-resistant advanced melanoma. 

In preclinical models from patients with treatment-resistant tumors, combining standard BRAF and MEK inhibitors with a drug to block proteins in the BCL2 family – which drive tumor growth – induced tumor regression in a molecularly defined subset of resistant tumors, suggesting a path toward biomarker-guided therapy. 

The study, published in Nature Communications, was led 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, M.D., Ph.D., chair of Melanoma Medical Oncology.

“Targeted therapy works by shutting down the main signal driving 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 to drug combinations tailored to their specific tumor biology.”

Why do certain melanomas become treatment-resistant?

Approximately half of all melanomas carry a mutation in the BRAF gene, which drives 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, roughly 80% of patients develop acquired resistance and disease progression within two years, potentially due to an increase in certain proteins within the BCL2 family.

Cancer cells often evade therapy 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 with most other cancer types, and that levels of BCL2 increase in patients following BRAF-MEK inhibitor therapies, 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 established 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 now regressed with the new combination in these models. 

Tumors with high baseline levels of BCL2 tended to respond, while tumors with high baseline MCL1 expression tended to resist. To confirm the role of MCL1, the researchers artificially raised its levels in tumor cells, which induced 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 in clinical practice?

MCL1 inhibitors previously have demonstrated antitumor activity but have been associated with heart-related side effects in early clinical trials, leading several studies to be paused or halted. In this study, adding BRAF-MEK inhibitors appeared to protect heart cells from the damaging effects of the MCL1 inhibitor. 

In laboratory models, the MCL1 inhibitor alone disrupted cardiac cell energy production and caused signs of damage. Adding BRAF and MEK inhibitors largely reversed these effects, potentially because the MEK inhibitor helped restore energy production in heart cells that MCL1 inhibitors otherwise disrupt. Further research is needed to determine whether this protective effect translates to patients.

“We did not anticipate that pairing these drugs would reduce MCL1 inhibitor toxicity,” Davies said. “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.”

What’s next for this research?

These findings support the design of biomarker-guided clinical trials that match patients to 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 BRAF-mutant melanoma patients 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,” 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.”

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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 a full list of collaborating authors, disclosures and funding sources, see the full paper in Nature Communications.