Malignant melanoma is one of the most common types of cancer in the United States. Despite improvements in therapeutics, advanced disease is often lethal if the cancer develops resistance to immune and targeted therapies. Metabolic reprogramming is an important hallmark of cancer and drives resistance to certain therapies. Previous efforts to modulate melanoma metabolism have focused on targeting glycolysis, whereas targeting mitochondrial oxidative phosphorylation (OXPHOS) and the TCA cycle is relatively less developed for melanoma.

Melanoma cell lines were evaluated under chemotherapy-associated stress using assays of mitochondrial function and oxidative metabolism. Pharmacologic inhibition of the mitochondrial electron transport chain was assessed using complex I inhibitors in combination with conventional anti-melanoma chemotherapy in preclinical in vitro models, with validation in animal models.

Melanoma cells rely heavily on mitochondrial function, particularly under chemotherapy-associated stress, as evidenced by increased OXPHOS activity. Pharmacologic inhibition of the mitochondrial electron transport chain (ETC) with complex I inhibitors (Phenformin and IACS-010759) synergizes with conventional anti-melanoma chemotherapy in pre-clinical in vitro models of melanoma, with added benefit in animal models.

These findings suggest that melanoma adapts to chemotherapy by increasing mitochondrial oxidative metabolism. Targeting the ETC offers a compelling strategy to enhance chemotherapy activity in patients with advanced and treatment-refractory melanoma.