Molecular Pathways: Isocitrate Dehydrogenase Mutations in Cancer

IDH1 and IDH2 are homodimeric enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (α-KG) and concomitantly produce reduced NADPH from NADP(+) Mutations in the genes encoding IDH1 and IDH2 have recently been found in a variety of human cancers, most commonly glioma, acute myeloid le...

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Bibliographic Details
Published in:Clinical cancer research 2016-04, Vol.22 (8), p.1837-1842
Main Authors: Clark, Owen, Yen, Katharine, Mellinghoff, Ingo K
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Cell Transformation, Neoplastic
Humans
Isocitrate Dehydrogenase - antagonists & inhibitors
Isocitrate Dehydrogenase - genetics
Isocitrate Dehydrogenase - metabolism
Molecular Targeted Therapy
Mutation
Neoplasms - drug therapy
Neoplasms - genetics
Neoplasms - metabolism
Signal Transduction
Translational Medical Research
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Summary:IDH1 and IDH2 are homodimeric enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (α-KG) and concomitantly produce reduced NADPH from NADP(+) Mutations in the genes encoding IDH1 and IDH2 have recently been found in a variety of human cancers, most commonly glioma, acute myeloid leukemia (AML), chondrosarcoma, and intrahepatic cholangiocarcinoma. The mutant protein loses its normal enzymatic activity and gains a new ability to produce the "oncometabolite" R(-)-2-hydroxyglutarate (R-2-HG). R-2-HG competitively inhibits α-KG-dependent enzymes which play crucial roles in gene regulation and tissue homeostasis. Expression of mutant IDH impairs cellular differentiation in various cell lineages and promotes tumor development in cooperation with other cancer genes. First-generation inhibitors of mutant IDH have entered clinical trials, and have shown encouraging results in patients with IDH-mutant AML. This article summarizes recent progress in our understanding of the role of mutant IDH in tumorigenesis.Clin Cancer Res; 22(8); 1837-42. ©2016 AACR.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.ccr-13-1333