Melanoma’s excessive mitochondrial dependence becomes a therapeutic vulnerability

Researchers have discovered that the most aggressive melanomas, the deadliest form of skin cancer, overactivate two key processes in mitochondria, the components of cells that provide energy. Blocking these pathways with currently available drugs effectively killed melanoma cells. The findings are published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.

By mapping the proteins expressed in 151 tumor and normal skin samples, investigators found that the most aggressive melanomas hyper-activate the machinery that builds mitochondrial proteins and the mitochondrial system that turns nutrients into energy.

Remarkably, blocking these pathways effectively halted or killed melanoma cells cultured in lab dishes. Two types of drugs accomplished this: antibiotics-originally designed to block bacterial protein synthesis machinery, which closely resembles the machinery found in mitochondria-and specialized energy-production inhibitors. Importantly, non-cancerous skin cells remained mostly unaffected, highlighting the safety and specificity of these treatment approaches.

This discovery identifies melanoma's excessive reliance on mitochondrial energy as its Achilles' heel, revealing a therapeutic vulnerability that we can exploit with existing drugs. By pairing mitochondrial blockers with today's standards of care, we may cut off a major escape route that cancers use to resist therapy and come back."

Jeovanis Gil, PhD, senior author of Lund University, Sweden

Dr. Gil added that the mitochondrial-protein signature his team discovered can be measured in routine biopsy material and could serve as a biomarker to identify patients most likely to benefit from mitochondrial-targeted add-on therapies. By enabling clinicians to match treatments to each patient's tumor biology, these findings mark a step forward for precision medicine in melanoma. Moreover, because mitochondrial rewiring fuels resistance across many cancers, success in melanoma could open the door to similar personalized combination strategies in other hard-to-treat cancers.