Abstract 872: IDH1-mutated cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity

Abstract

Abstract Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human cancer and predicts improved response to treatment with irradiation or chemotherapy. Mutated IDH1 enzymes catalyze neomorphic conversion of α-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (D-2HG) with concomitant consumption of NADPH, resulting in decreased reducing power needed for detoxification of e.g. reactive oxygen species (ROS). We report that a small-molecule inhibitor of IDH1-mutation (IDH1MUT) that is being investigated for cancer therapy may limit efficacy of treatment when co-administered with cisplatin. In the present study, we investigated whether the efficacy of treatment with cisplatin, which is a widely-used chemotherapeutic agent, induces DNA strand breaks and oxidative damage in IDH1MUT cancer cells. We found that exposure to cisplatin induced higher levels of ROS, DNA double-strand breaks, and cell death in IDH1MUT cancer cells as compared to IDH1 wild-type (IDH1WT) cancer cells. Besides these cytotoxic effects, mechanistic investigations revealed that cisplatin treatment causes dose-dependent reduction of oxygen consumption and thus the oxidative respiration in lDH1MUT cells and not in lDH1WT cells, which was accompanied by disturbed mitochondrial proteostasis and impaired mitochondrial activity. These effects were abolished by the IDH1MUT inhibitor AGI-5198 and were recapitulated by treatment with D-2HG. Thus, our study shows that altered oxidative stress responses due to a vulnerable oxidative metabolism underlie the sensitivity of IDH1MUT cancer cells to cisplatin. Furthermore, our data offer an explanation for the relatively longer survival of patients with IDH1-mutated tumors, and imply that administration of IDH1MUT inhibitors in these patients limit efficacy of cisplatin treatment. Citation Format: Mohammed Khurshed, Remco J. Molenaar, Johanna W. Wilmink, Hanneke W. van Laarhoven, Cornelis J. van Noorden. IDH1-mutated cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 872.