Melanoma Study Identifies Metabolic Vulnerability to Improve Chemotherapy Response
Case CCC investigators Mehrdad Zarei, PhD, MBA (pictured), Rui Wang, PhD, member of Case CCC’s Molecular Oncology Program, Jordan Winter, MD, co-leader of Case CCC’s Developmental Therapeutics Program, and Luke Rothermel, MD, MPH, member of Case CCC’s Immune Oncology Program recently published findings in the Journal of Experimental & Clinical Cancer Research demonstrating how melanoma adapts to chemotherapy through metabolic reprogramming.
In the study, “Melanoma resists chemotherapy through an adaptive mitochondrial response,” the team identified mitochondrial oxidative phosphorylation (OXPHOS) as a key survival mechanism that allows melanoma cells to adapt to chemotherapy-associated stress.
Researchers found that melanoma cells shift their metabolism toward increased mitochondrial activity during treatment, suggesting mitochondrial function plays a significant role in chemoresistance.
To test whether disrupting this adaptive response could improve treatment outcomes, investigators evaluated the mitochondrial complex I inhibitors Phenformin and IACS-010759 in combination with conventional anti-melanoma chemotherapy. In both cell line and animal models, inhibition of mitochondrial electron transport chain activity enhanced chemotherapy sensitivity and demonstrated synergistic anti-tumor effects.
The findings support mitochondrial metabolism as a promising therapeutic target in treatment-resistant melanoma and provide rationale for further investigation of combination strategies pairing chemotherapy with metabolic inhibitors.
Additional co-authors include: Alexander Loftus, MD, Sami Abul-Khoudoud, MD, John Asara, PhD, Faith Nakazzi, Semmer Ali, Hallie Graor, and Om Prajapati.