IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives

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.

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.