Targeting cytosolic mutant IDH1 by hyperactivation to induce cancer cytotoxicity

Somatic mutations in isocitrate dehydrogenase (IDH) enzymes are hallmarks of acute myeloid leukemia (AML), glioma, and several other cancers. Mutant IDH enzymes lose their normal function of catalyzing NADP(H)-dependent conversion of isocitrate to alpha-ketoglutarate (alpha-KG) and instead gain an abnormal new activity that reduces alpha-KG to 2-hydroxyglutarate (2HG), an oncometabolite that drives chromatin hypermethylation and blocks differentiation. Although FDA-approved inhibitors such as ivosidenib and enasidenib effectively suppress 2HG, fewer than half of patients respond, and resistance invariably develops. We discovered that genetic or pharmacologic hyperactivation, rather than inhibition, of mitochondrial mutant IDH2 triggers lethal metabolic toxicity that selectively eliminates IDH2-mutant cancer cells. Building on these findings, we hypothesized that hyperactivation of cytosolic mutant IDH1 could similarly cause toxic 2HG accumulation, redox imbalance, and selective death of IDH1-mutant cancer cells. To test this hypothesis, we engineered human cancer cell lines with inducible expression of hyperactive IDH1 mutants, which resulted in excessive 2HG production, metabolic dysfunction, and impaired cell fitness. In parallel, we found that activation of mitochondrial 2HG production in IDH1-mutant cancer cells triggers profound metabolic collapse, leading to impaired cell growth in vitro and in vivo. Together, these results suggest that direct or indirect hyperactivation of the mutant IDH1 pathway may represent a new therapeutic strategy --- targeting cytosolic IDH1 mutations by driving cancer cells beyond their metabolic limits.