Hyperthermia as a Potential Cornerstone of Effective Multimodality Treatment with Radiotherapy, Cisplatin and PARP Inhibitor in IDH1-Mutated Cancer Cells

Mutations in the isocitrate dehydrogenase 1 (IDH1^MUT) gene occur in various types of malignancies, including ~60% of chondrosarcomas, ~30% of intrahepatic cholangiocarcinomas and >80% of low-grade gliomas. IDH1^MUT are causal in the development and progression of these types of Cancer due to neomorphic production of the oncometabolite D-2-hydroxyglutarate (D-2HG). Intracellular accumulation of D-2HG has been implicated in suppressing homologous recombination and renders IDH1^MUT Cancer cells sensitive to DNA-repair-inhibiting agents, such as poly-(adenosine 5'-diphosphate-ribose) polymerase inhibitors (PARPi). Hyperthermia increases the efficacy of DNA-damaging therapies such as radiotherapy and platinum-based chemotherapy, mainly by inhibition of DNA repair. In the current study, we investigated the additional effects of hyperthermia (42 °C for 1 h) in the treatment of IDH1^MUT HCT116 colon Cancer cells and hyperthermia1080 chondrosarcoma Cancer cells in combination with radiation, cisplatin and/or a PARPi on clonogenic cell survival, cell cycle distribution and the induction and repair of DNA double-strand breaks. We found that hyperthermia in combination with radiation or cisplatin induces an increase in double-strand breaks and cell death, up to 10-fold in IDH1^MUT Cancer cells compared to IDH1 wild-type cells. This vulnerability was abolished by the IDH1^MUT inhibitor AGI-5198 and was further increased by the PARPi. In conclusion, our study shows that IDH1^MUT Cancer cells are sensitized to hyperthermia in combination with irradiation or cisplatin and a PARPi. Therefore, hyperthermia may be an efficacious sensitizer to cytotoxic therapies in tumors where the clinical application of hyperthermia is feasible, such as IDH1^MUT chondrosarcoma of the extremities.

D-2-hydroxyglutarate; PARP; cisplatin; hyperthermia; isocitrate dehydrogenase; radiotherapy.