Targeting Isocitrate Dehydrogenase (IDH) in cancer

Takeo Fujii, Muhammad Rizwan Khawaja, Courtney D. DiNardo, Johnique T. Atkins, Filip Janku

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

Isocitrate dehydrogenase (IDH) is an essential enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle. Recurrent mutations in IDH1 or IDH2 are prevalent in several cancers including glioma, acute myeloid leukemia (AML), cholangiocarcinoma, and chondrosarcoma. The mutated IDH1 and IDH2 proteins have a gain-of-function, neomorphic activity, catalyzing the reduction of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG) by NADPH. Cancer-associated IDH mutations block normal cellular differentiation and promote tumorigenesis via the abnormal production of the oncometabolite 2-HG. High levels of 2-HG have been shown to inhibit α-KG dependent dioxygenases, including histone and deoxyribonucleic acid (DNA) demethylases, which play a key role in regulating the epigenetic state of cells. Current targeted inhibitors of IDH1 (AG120, IDH305), IDH2 (AG221), and pan-IDH1/2 (AG881) selectively inhibit mutant IDH protein and induce cell differentiation in in vitro and in vivo models. Preliminary results from phase I clinical trials with IDH inhibitors in patients with advanced hematologic malignancies have demonstrated an objective response rate ranging from 31% to 40% with durable responses (> 1 year) observed. Furthermore, the IDH inhibitors have demonstrated early signals of activity in solid tumors with IDH mutations, including cholangiocarcinomas and low grade gliomas.

Original languageEnglish (US)
Pages (from-to)373-380
Number of pages8
JournalDiscovery Medicine
Volume21
Issue number117
StatePublished - 2016

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Fingerprint Dive into the research topics of 'Targeting Isocitrate Dehydrogenase (IDH) in cancer'. Together they form a unique fingerprint.

Cite this