Journal of Blood Medicine (Sep 2016)
IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives
Abstract
Johanna Mondesir1,2 Christophe Willekens3–5 Mehdi Touat6,7 Stéphane de Botton3–5 1Service d’Immunopathologie Clinique, Hôpital Saint Louis, 2CNRS UMR8104, INSERM U1016, Institut Cochin, Université Paris Descartes, Paris, 3Gustave Roussy, Université Paris-Saclay, Service d’Hématologie Clinique, 4INSERM U1170, Gustave Roussy, Université Paris-Saclay, Villejuif, 5Faculté de médecine Paris-Sud, Kremlin-Bicêtre, 6AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière – Charles Foix, Service de Neurologie 2-Mazarin, Paris, 7Gustave Roussy, Université Paris‑Saclay, Département d’Innovation Thérapeutique et d’Essais Précoces, Villejuif, France 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: tumor metabolism, epigenetic, oncogene, IDH1, IDH2, glioma, acute myeloid leukemia, 2-HG, targeted therapies
