Isocitrate Dehydrogenase Mutations in Cancer: Mechanisms of Transformation and Metabolic Liability.

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are metabolic enzymes that interconvert isocitrate and 2-oxoglutarate (2OG). Gain-of-function mutations in and occur in a number of cancers, including acute myeloid leukemia, glioma, cholangiocarcinoma, and chondrosarcoma. These mutations cripple the wild-type activity of IDH and cause the enzymes to catalyze a partial reverse reaction in which 2OG is reduced but not carboxylated, resulting in production of the ()-enantiomer of 2-hydroxyglutarate (()-2HG). ()-2HG accumulation in tumors results in profound dysregulation of cellular metabolism. The most well-characterized oncogenic effects of ()-2HG involve the dysregulation of 2OG-dependent epigenetic tumor-suppressor enzymes. However, ()-2HG has many other effects in cells, some that promote transformation and others that induce metabolic dependencies. Herein, we review how cancer-associated mutations impact epigenetic regulation and cellular metabolism and discuss how these effects can potentially be leveraged to therapeutically target tumors.