Biomarker-guided combinations show promise in treatment-resistant melanoma

Vashisht Gopal Yennu Nanda, Ph.D. Photo courtesy of The University of Texas MD Anderson Cancer Center

Researchers at The University of Texas MD Anderson Cancer Center report that tailoring targeted drug combinations to tumour dependence on BCL2 family proteins may restore treatment responses in patients with advanced melanoma that has progressed on standard BRAF-MEK therapy. These personalized strategies may improve outcomes in this challenging patient population and, in addition, potentially mitigate cardiotoxicity associated with experimental MCL1 inhibition.

Their findings were published in Nature Communications.

There are currently no effective targeted therapies for BRAF-mutant metastatic melanoma patients with acquired resistance to approved BRAF and MEK inhibitors (BRAFi and MEKi), and very few ongoing clinical trials. 

In this preclinical program using patient-derived xenograft models of BRAF-mutant melanoma with acquired resistance, investigators added a BCL2 inhibitor, navitoclax or venetoclax, to dabrafenib–trametinib and observed regression in a molecularly defined subset of tumours. Tumours with high baseline BCL2 expression tended to respond, whereas those characterized by elevated MCL1 expression remained refractory; enforced MCL1 overexpression induced resistance to the triple regimen, underscoring divergent survival dependencies within the BCL2 family.

To address MCL1-driven disease, the group tested an alternative combination pairing BRAF-MEK inhibition with the investigational MCL1 inhibitor AZD5991, achieving complete regression in a high-MCL1 xenograft model with no detectable tumours at study end.

Historically, MCL1 inhibitors have shown antitumour activity but have been constrained by cardiac adverse effects in early-phase trials, prompting pauses and terminations. In this work, BRAF-MEK coadministration appeared to reverse MCL1 inhibitor–induced disruption of cardiac cell energy production in laboratory models, suggesting a mechanistic basis for reduced cardiotoxicity. This characteristic will require further clinical confirmation, the researchers noted.

“Targeted therapy works by shutting down the main signal driving melanoma growth, but tumours often have backup systems that keep them alive,” Vashisht Gopal Yennu Nanda, PhD, the study’s lead author, said in a press release. “By identifying which protein a tumour relies on for survival, we may be able to match patients to drug combinations tailored to their specific tumour biology.”

Senior author Michael A. Davies, MD, PhD, noted that if the cardioprotective effects of BRAF-MEK inhibitors are borne out in trials, they “could give a second life to a class of drugs that has struggled to advance through development.”

The researchers believe these findings support biomarker-guided clinical trial designs stratified by BCL2 and MCL1 expression and ongoing analyses from a Phase 2 trial of dabrafenib, trametinib, and navitoclax in BRAF-mutant melanoma.