Targeting mitochondrial oxidative metabolism in melanoma causes metabolic compensation through glucose and glutamine utilization.

Metabolic targets offer attractive opportunities for cancer therapy. However, their targeting may activate alternative metabolic pathways that can still support tumor growth. A subset of human melanomas relies on PGC1α-dependent mitochondrial oxidative metabolism to maintain growth and survival. Herein, we show that loss of viability caused by suppression of PGC1α in these melanomas is rescued by induction of glycolysis. Suppression of PGC1α elevates reactive oxygen species levels decreasing hypoxia-inducible factor-1α (HIF1α) hydroxylation that, in turn, increases its protein stability. HIF1α reprograms melanomas to become highly glycolytic and dependent on this pathway for survival. Dual suppression of PGC1α and HIF1α causes energetic deficits and loss of viability that are partially compensated by glutamine utilization. Notably, triple suppression of PGC1α, HIF1α, and glutamine utilization results in complete blockage of tumor growth. These results show that due to high metabolic and bioenergetic flexibility, complete treatment of melanomas will require combinatorial therapy that targets multiple metabolic components.