title: Molecular Pathways: Isocitrate Dehydrogenase Mutations in Cancer.
abstract: 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.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Owen
authors.initials: O
authors.lastname: Clark
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Katharine
authors.initials: K
authors.lastname: Yen
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York. Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York. Department of Pharmacology, Weill-Cornell Graduate School of Biomedical Sciences, New York, New York. mellingi@mskcc.org.
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D057170:Translational Research, Biomedical
chemical_list: D000970:Antineoplastic Agents; D007521:Isocitrate Dehydrogenase
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