10166-CB-4 Evaluation of Radiation Response and 2-Hydroxyglutarate Suppression by IDH Inhibition in IDH Mutant Glioma Cells

Abstract Background IDH mutant gliomas accumulate the oncometabolite 2-hydroxyglutarate (2HG) via abnormal metabolic pathways, which contribute to tumor growth and epigenomic dysregulation. IDH inhibitors, such as AGI-5198, suppress 2HG production and have been approved by the FDA. While clinical application with radiotherapy (IR) is anticipated, preclinical data on optimal timing and therapeutic synergy remain limited. This study evaluated the effects of short-term (5 days) and long-term (more than 5 weeks) AGI-5198 treatment on the radiosensitivity of IDH mutant glioma cells. Methods We used the IDH1-R132H mutant fibrosarcoma cell line HT1080 and patient-derived glioma lines (MGG18, MGG119, MGG152, TS603). MGG18 is a tetracycline-inducible IDH1-R132H model activated by doxycycline (1 ug/mL). AGI-5198 was administered for short-term or long-term periods, followed by irradiation (0 to 20 Gy). Cell viability was evaluated using Cell Titer-Glo and colony formation assays. 2HG levels were quantified by fluorescence-based measurements. Results AGI-5198 reduced 2HG levels in all cell lines. Suppression was sustained during treatment but reverted to baseline within a week of withdrawal. Radiation alone induced dose-dependent cytotoxicity. However, radiosensitizing effects were not observed in most lines, regardless of AGI-5198 duration. Notably, BRCA1-mutant MGG152 cells showed increased radiosensitivity at radiation doses above 10 Gy following short-term AGI-5198. Conclusion AGI-5198 suppresses 2HG production but does not generally enhance radiosensitivity in IDH mutant glioma cells. The radiosensitization observed in BRCA1-mutant MGG152 suggests that DNA repair vulnerabilities may modulate response. Long-term treatment does not appear to significantly impact radiation effects in most models.