Researchers at the University of Texas MD Anderson Cancer Center have identified a strategy to reverse resistance to standard treatment in BRAF-mutant advanced melanoma. Their findings, published today in Nature Communications, support using a biomarker-guided approach to improve outcomes for patients with treatment-resistant melanoma.
“Patients whose melanoma has stopped responding to standard therapies currently have very few effective treatment options,” said Vashisht Gopal Yennu Nanda, PhD, associate professor of melanoma medical oncology and translational molecular pathology at UT MD Anderson. “Our findings could help address this critical need for these patients by guiding clinicians toward combinations tailored to each individual’s tumors.”
About 50% of melanoma tumors carry BRAF mutations that drive uncontrolled tumor growth. Although the standard of care, consisting of a combination of BRAF and MEK inhibitors, is initially effective in most patients, about 80% will develop resistance within two years. In many cancers, but especially in melanoma, acquired resistance is often driven by the tumor increasing production of proteins from the BCL2 family, which block apoptosis and support the survival of cancer cells.
Yennu Nanda and colleagues tested the effects of adding a BCL2 inhibitor drug to the standard two-drug regimen in patient-derived xenograft models, which were established using melanoma tumors that had acquired resistance to standard therapy. Results showed that tumors that expressed high levels of BCL2 responded well to the triple combination, reversing resistance and inducing a complete tumor regression.
However, tumors that expressed high levels of MCL1—another protein from the BCL2 family—did not respond to this combination. In these tumors, the researchers tested an alternative treatment course adding an experimental MCL1 inhibitor to standard treatment, which successfully led to complete tumor regression.
“Targeted therapy works by shutting down the main signal driving melanoma growth, but tumors often have backup systems that keep them alive,” said Yennu Nanda. “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.”
MCL1 inhibitors have previously shown promising antitumor activity, but early clinical trials flagged concerning heart-related side effects that have prevented them from moving through clinical development and receiving approval. In this study, however, the combination of an MCL1 inhibitor with standard BRAF-MEK inhibitors seemed to protect cardiac cells from the harmful effects associated with these experimental drugs.
“We did not anticipate that pairing these drugs would reduce MCL1 inhibitor toxicity,” said Michael A. Davies, MD, PhD, chair of melanoma medical oncology at UT MD Anderson. “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.”
Building on these findings, the researchers are now working on analyzing tumor samples from a recent Phase II clinical trial in melanoma patients who received standard treatment and a BCL2 inhibitor, with the goal of studying whether MCL1 expression can predict clinical response. Down the line, their goal is to design clinical trials where melanoma patients are matched with drug combinations based on the expression of BCL2 or MCL1 biomarkers.
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