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.

Figure 1. Co-occuring genetic lesions in IDH-mutant glioma and AML

Oncoprint figure (generated using Memorial Sloan Kettering cBio Portal)(10) showing frequency of commonly co-occuring genetic lesions in glioma (top) and AML (bottom). Note that TET2 is shown to illustrate near complete mutual exclusivity with mutations in IDH1/2. Results are based upon data generated by the TCGA Research Network: Glioma data set (32); AML data set (73). For simplicity changes in copy number were not included. TET2 - Tet Methylcytosine Dioxygenase 2; DNMT3A - DNA (Cytosine-5-)-Methyltransferase 3 Alpha; FLT3 - Fms-Related Tyrosine Kinase 3; NPM1 - Nucleophosmin (Nucleolar Phosphoprotein B23, Numatrin); TP53 - Tumor Protein P53; ATRX - Alpha Thalassemia/Mental Retardation Syndrome X-Linked.

Figure 2. Molecular mechanisms of IDH-associated tumorigenesis

Wild-type IDH1/2 (wtIDH1/2) converts isocitrate (generated through the citric acid (TCA) cycle) into α-KG, producing NADPH in the process. Mutant IDH1/2 (mutIDH1/2) converts α-KG to the oncometabolite R-2-HG, consuming NADPH. R-2-HG inhibits members of the protein family of α-KG-dependent dioxygenases. Epigenetic modifications result from inhibition of histone lysine demethylases (KDMs) and the 5-methyl cytosine hydroxylase TET2. Inhibition of prolyl-hydroxylation impairs collagen maturation. R-2-HG has been reported to activate the enzyme prolyl-hydroxylase 2 (PHD2) that inhibits hypoxia-inducible factor 1-alpha (HIF-1α) (22), although other studies suggest that it may be inhibited (46, 47). Mutant IDH may also change the cellular redox environment by altering the ratio of NADPH to NADP⁺. IDH3 has been omitted from this figure for simplicity.