Pyruvate and Metabolic Flexibility: Illuminating a Path Toward Selective Cancer Therapies

Dysregulated metabolism is an emerging hallmark of cancer, and there is abundant interest in developing therapies to selectively target these aberrant metabolic phenotypes. Sitting at the decision-point between mitochondrial carbohydrate oxidation and aerobic glycolysis (i.e., the ‘Warburg effect’), the synthesis and consumption of pyruvate is tightly controlled and is often differentially regulated in cancer cells. This review examines recent efforts toward understanding and targeting mitochondrial pyruvate metabolism, and addresses some of the successes, pitfalls, and significant challenges of metabolic therapy to date.

TrendsThe ability of cells to respond to different nutrient conditions and energetic demands is known as ‘metabolic flexibility’ and is an essential feature of normal cellular physiology.Adaptations that occur during the process of cancer formation may limit the metabolic flexibility of some cancers.Metabolic therapies designed to target cancers are predicated on the hypothesis that some cancers are less metabolically flexible than normal tissues, and this may be a means to selectively target cancer while sparing other tissues.Pyruvate metabolism is a central, differentially regulated, nexus of carbon metabolism that both provides and limits flexibility in normal and cancer tissues.