Genetic driver events in cancer activate signaling pathways that alter cell metabolism, and clinical evidence has linked metabolism with cancer outcomes. Together, this has raised interest in targeting metabolic enzymes for cancer therapy. The best strategy to target cancer metabolism, however, remains unclear. Cancer cells exhibit altered metabolism to efficiently incorporate nutrients into biomass to support proliferation. The M2 isoform of pyruvate kinase (PK-M2) promotes anabolic metabolism and is selected for optimal tumor growth in vivo. Paradoxically, the ability of PK-M2 to promote anabolic metabolism is associated with decreased pyruvate kinase enzyme activity, and genetically engineered mouse cancer models support the notion that loss of pyruvate kinase activity favors tumor growth. Nevertheless, the ability to reactivate pyruvate kinase may also be important for some tumor cells. These findings suggest that pyruvate kinase activity modulation may be a strategy to target cancer. Results from studies using small molecule activators of PK-M2 to restore the high pyruvate kinase activity found in most normal tissues will be presented. How these and associated studies inform efforts to target glucose metabolism for cancer therapy will also be discussed.

Modulation of pyruvate kinase activity and its role in cell metabolism

242nd National Meeting (2011)

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