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Review
. 2016 Sep 2:7:171-80.
doi: 10.2147/JBM.S70716. eCollection 2016.

IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives

Johanna Mondesir  1 , Christophe Willekens  2 , Mehdi Touat  3 , Stéphane de Botton  2
Affiliations
Review

IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives

Johanna Mondesir et al. J Blood Med. .

Abstract

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that convert isocitrate to α-ketoglutarate. IDH1/2 mutations define distinct subsets of cancers, including low-grade gliomas and secondary glioblastomas, chondrosarcomas, intrahepatic cholangiocarcinomas, and hematologic malignancies. Somatic point mutations in IDH1/2 confer a gain-of-function in cancer cells, resulting in the accumulation and secretion in vast excess of an oncometabolite, the D-2-hydroxyglutarate (D-2HG). Overproduction of D-2HG interferes with cellular metabolism and epigenetic regulation, contributing to oncogenesis. Indeed, high levels of D-2HG inhibit α-ketoglutarate-dependent dioxygenases, including histone and DNA demethylases, leading to histone and DNA hypermethylation and finally a block in cell differentiation. Furthermore, D-2HG is a biomarker suitable for the detection of IDH1/2 mutations at diagnosis and predictive of the clinical response. Finally, mutant-IDH1/2 enzymes inhibitors have entered clinical trials for patients with IDH1/2 mutations and represent a novel drug class for targeted therapy.

Keywords: 2-HG; IDH1; IDH2; acute myeloid leukemia; epigenetic; glioma; oncogene; targeted therapies; tumor metabolism.

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Figures

Figure 1
Figure 1
Enzymatic activities of wild type and mutated IDH enzymes. Notes: The IDH family of enzymes comprises three proteins located in the cytoplasm and peroxysomes (IDH1), and mitochondria (IDH2 and IDH3). IDH1 and IDH2 catalyze the reversible NADP+-dependent oxidative decarboxylation of isocitrate to αKG. IDH3 catalyzes the NAD+-dependent conversion of isocitrate to αKG in the TCA cycle. IDH1 and IDH2 mutant enzymes gain neomorphic enzymatic activity, converting NADPH and αKG to NADP+ and D-2HG. D-2HG acts as a weak competitive inhibitor of αKG-dependent dioxygenases. αKG-dependent dioxygenases are involved in various cellular processes such as hypoxia, angiogenesis, maturation of collagens of the extracellular matrix, and regulation of epigenetics. Excess of D-2HG is associated with increased histone and DNA methylation, altering cancer cells differentiation. Abbreviations: αKG, alpha ketoglutarate; D-2HG, D-2-hydroxyglutarate; IDH, isocitrate dehydrogenase; DNA, deoxyribonucleic acid; mut, mutated; NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; TCA cycle, tricarboxylic acid cycle.
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References

    1. Sjöblom T, Jones S, Wood LD, et al. The consensus coding sequences of human breast and colorectal cancers. Science. 2006;314(5797):268–274. - PubMed
    1. Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807–1812. - PMC - PubMed
    1. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–773. - PMC - PubMed
    1. Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361(11):1058–1066. - PMC - PubMed
    1. Kosmider O, Gelsi-Boyer V, Slama L, et al. Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia. 2010;24(5):1094–1096. - PubMed