Biological Role and Therapeutic Potential of IDH Mutations in Cancer
Matthew S Waitkus1, Bill H Diplas1, Hai Yan1
1Department of Pathology, Duke University, Durham, NC, USA; The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC, USA.
Abstract:
Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) occur in a variety of myeloid malignancies and solid tumors. Mutant IDH proteins acquire a neomorphic enzyme activity to produce the putative oncometabolite D-2-hydroxyglutarate, which is thought to block cellular differentiation by competitively inhibiting α-ketoglutarate-dependent dioxygenases involved in histone and DNA demethylation. Small-molecule inhibitors of mutant IDH1 and IDH2 have been developed and are progressing through pre-clinical and clinical development. In this review, we provide an overview of mutant IDH-targeted therapy and discuss a number of important recent pre-clinical studies using models of IDH-mutant solid tumors.
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