Biological Role and Therapeutic Potential of IDH Mutations in Cancer

Cancer Cell. 2018 Aug 13;34(2):186-195. doi: 10.1016/j.ccell.2018.04.011. Epub 2018 May 24.

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.

Keywords: 2-hydroxyglutarate; acute myeloid leukemia; cancer therapy; glioblastoma; glioma; isocitrate dehydrogenase.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Glioma / drug therapy
  • Humans
  • Isocitrate Dehydrogenase / antagonists & inhibitors
  • Isocitrate Dehydrogenase / genetics*
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics
  • Mice
  • Mutation*
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • TOR Serine-Threonine Kinases / physiology

Substances

  • IDH2, human
  • Isocitrate Dehydrogenase
  • TOR Serine-Threonine Kinases