Abstract 7081: Enzyme hyperactivation to target isocitrate dehydrogenase mutations

Abstract Somatic mutations in isocitrate dehydrogenase (IDH) enzymes are hallmarks of acute myeloid leukemia (AML), glioma, and several other cancers. Mutations in IDH result in the neomorphic ability to convert alpha-ketoglutarate (α-KG) into the oncometabolite 2-hydroxyglutarate (2HG), which competitively inhibits α-KG-dependent enzymes and locks malignant cells in a stem cell-like state. Targeted inhibition of mutant IDH enzymes effectively shuts off production of the oncometabolite 2HG and benefits some patients with IDH-mutant cancers. However, the majority of IDH-mutant tumors are impervious to 2HG inhibition. Even for those cases that respond to mutant IDH inhibition, drug resistance invariably develops. Thus, there is an unmet need for novel therapeutic approaches beyond simple inhibition of mutant IDH. Based on mechanistic studies of an unusual drug resistance mutation identified in patients with acquired resistance to IDH inhibitors, we discovered that genetic hyperactivation of mutant IDH2 converts the activity of mutant IDH2 into a lethal metabolic liability. Using chemical screens, we identified small molecules that hyperactivate mutant IDH2, unleash metabolic toxicity, and selectively eliminate IDH2-mutant cancer cells. Thus, we propose that hyperactivation (rather than inhibition) of mutant IDH offers an unexpected and effective new therapeutic approach for targeting IDH-mutant cancers. Citation Format: Erick Gonzalez, Shengqi Hou, Andrew M. Intlekofer. Enzyme hyperactivation to target isocitrate dehydrogenase mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7081.