Effects of short- and long-term mutant IDH1 inhibition on radiosensitivity across genetically diverse patient-derived IDH1-mutant glioma cells.

IDH mutant gliomas produce the oncometabolite 2-hydroxyglutarate (2-HG), driving tumorigenesis through metabolic dysregulation and epigenetic alterations. IDH inhibitors (IDHi) reduce 2-HG and are clinically approved for treating IDH mutant gliomas. However, the observed impact of IDHi therapy on tumor response to ionizing radiation (IR) has been variable across murine models and engineered cell lines. We investigated the effects of short-term (5 days) and long-term (≥5 weeks) exposure to the IDH1 inhibitor AGI-5198 on radiation-induced cytotoxicity. Patient-derived glioma neurosphere lines (MGG119, TS603S2, BT142, and MGG152) were studied, with IDH1-mutant fibrosarcoma HT1080 and an inducible IDH1-R132H glioma line (MGG18 Tet±). Intracellular 2-HG, cell viability, and clonogenic survival were measured following IR. AGI-5198 potently reduced intracellular 2-HG across all IDH1-mutant lines after short-term treatment, with suppression maintained during prolonged exposure but rapidly reversed upon withdrawal. Long-term AGI exposure produced cell viability responses to both standard- and high-dose IR comparable to short-term treatment in HT1080, TS603S2, BT142, MGG152, and MGG18 Tet±. Across endogenous IDH-mutant models, neither short- nor long-term IDH inhibition induced radioresistance. MGG119, harboring IDH1-R132H and MET alterations, showed intrinsic radioresistance unaffected by IDHi. In contrast, MGG152, harboring IDH1-R132H and BRCA2 mutations, exhibited modest radiosensitization with IDHi. Prolonged AGI-5198 exposure does not reduce IR sensitivity in IDH mutant glioma cells. Effects were comparable to short-term treatment, while radiation responses varied by genetic context. No deleterious interaction between IDHi and IR was observed in endogenous IDH-mutant cells except for MGG18 Tet+ supporting integration of IDHi with radiotherapy in IDH mutant gliomas.