Molecular Targeting of the Isocitrate Dehydrogenase Pathway and the Implications for Cancer Therapy

The advent of comprehensive genomic profiling using next-generation sequencing (NGS) has unveiled an abundance of potentially actionable genetic aberrations that have shaped our understanding of the cancer biology landscape. Isocitrate dehydrogenase (IDH) is an enzyme present in the cytosol (IDH1) and mitochondria (IDH2 and IDH3). In the mitochondrion, it catalyzes the irreversible oxidative decarboxylation of isocitrate, yielding the production of α-ketoglutarate and nicotinamide adenine dinucleotide phosphate (NADPH) as well as carbon dioxide (CO₂). In the cytosol, IDH catalyzes the decarboxylation of isocitrate to α-ketoglutarate as well as the reverse reductive carboxylation of α-ketoglutarate to isocitrate. These rate-limiting steps in the tricarboxylic acid cycle, as well as the cytoplasmic response to oxidative stress, play key roles in gene regulation, cell differentiation, and tissue homeostasis. Mutations in the genes encoding IDH1 and IDH2 and, less commonly, IDH3 have been found in a variety of cancers, most commonly glioma, acute myeloid leukemia (AML), chondrosarcoma, and intrahepatic cholangiocarcinoma. In this paper, we intend to elucidate the theorized pathophysiology behind IDH isomer mutation, its implication in cancer manifestation, and discuss some of the available clinical data regarding the use of novel IDH inhibitors and their role in therapy.