IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives.
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.
Service d'Immunopathologie Clinique, Hôpital Saint Louis; CNRS UMR8104, INSERM U1016, Institut Cochin, Université Paris Descartes, Paris.
Johanna
J
Mondesir
Gustave Roussy, Université Paris-Saclay, Service d'Hématologie Clinique; INSERM U1170, Gustave Roussy, Université Paris-Saclay, Villejuif; Faculté de médecine Paris-Sud, Kremlin-Bicêtre.
Christophe
C
Willekens
AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris; Gustave Roussy, Université Paris-Saclay, Département d'Innovation Thérapeutique et d'Essais Précoces, Villejuif, France.
Mehdi
M
Touat
Gustave Roussy, Université Paris-Saclay, Service d'Hématologie Clinique; INSERM U1170, Gustave Roussy, Université Paris-Saclay, Villejuif; Faculté de médecine Paris-Sud, Kremlin-Bicêtre.
Stéphane
S
de Botton
2-HG; IDH1; IDH2; acute myeloid leukemia; epigenetic; glioma; oncogene; targeted therapies; tumor metabolism