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.

Matthew S Waitkus ¹, Bill H Diplas ¹, Hai Yan ²

Affiliations

1 Department of Pathology, Duke University, Durham, NC, USA; The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC, USA.
2 Department of Pathology, Duke University, Durham, NC, USA; The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC, USA. Electronic address: [email protected].

PMID: 29805076 DOI: 10.1016/j.ccell.2018.04.011

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.

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