IDH2

IDH2, or isocitrate dehydrogenase 2, is a mitochondrial enzyme that catalyzes the NADP+-dependent oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG), generating NADPH in the process. It contributes to the TCA cycle and helps maintain cellular redox balance and biosynthetic capacity.

Mutations in IDH2 occur in several cancers, most notably acute myeloid leukemia (AML), cholangiocarcinoma, and chondrosarcoma. In gliomas, IDH1 mutations are more common than IDH2 mutations. Mutant IDH2 enzymes acquire a neomorphic activity that reduces α-KG to 2-hydroxyglutarate (2-HG) using NADPH. The accumulation of 2-HG inhibits α-KG–dependent dioxygenases, leading to widespread epigenetic changes, altered DNA and histone methylation, and impaired cellular differentiation.

Common hotspot mutations in IDH2 include codons 140 and 172 (for example R140Q and R172K). These mutations are associated with a distinct biology and have become clinically actionable targets in specific cancers.

Therapeutically, IDH2 mutations in AML have led to the development of targeted inhibitors, the most prominent being enasidenib (AG-221). Enasidenib selectively inhibits mutant IDH2, lowers 2-HG levels, and promotes differentiation of malignant cells. It has been approved for adults with relapsed or refractory IDH2-mutant AML and is used in combination or sequence with other therapies in various treatment settings. Ongoing research explores IDH2 inhibitors in other IDH2-mutant tumors and mechanisms of resistance and combination strategies.

Diagnosis typically involves sequencing the IDH2 gene in tumor samples to determine mutation status and guide the use of IDH2-targeted therapies.