Molecular Pathways: Isocitrate Dehydrogenase Mutations in Cancer

被引：149

作者：

Clark, Owen ^{[1
]}

Yen, Katharine ^{[2
]}

Mellinghoff, Ingo K. ^{[1
,3
,4
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA

[2] Agios Pharmaceut, Cambridge, MA USA

[3] Mem Sloan Kettering Canc Ctr, Dept Neurol, 1275 York Ave, New York, NY 10021 USA

[4] Weill Cornell Grad Sch Biomed Sci, Dept Pharmacol, New York, NY USA

来源：

CLINICAL CANCER RESEARCH | 2016年 / 22卷 / 08期

关键词：

ACUTE MYELOID-LEUKEMIA; IDH MUTANT GLIOMAS; ONCOMETABOLITE; 2-HYDROXYGLUTARATE; PROMOTES DIFFERENTIATION; GENOMIC ANALYSIS; CELL-GROWTH; D-2-HYDROXYGLUTARATE; INHIBITION; FREQUENT; MICE;

D O I：

10.1158/1078-0432.CCR-13-1333

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

IDH1 and IDH2 are homodimeric enzymes that catalyze the conversion of isocitrate to alpha-ketoglutarate (alpha-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 cholangio-carcinoma. 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 alpha-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. (C) 2016 AACR.

引用

页码：1837 / 1842

页数：6

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