| Autor: |
Khurshed M; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands., Prades-Sagarra E; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands., Saleh S; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands., Sminia P; Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands., Wilmink JW; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands., Molenaar RJ; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands.; Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands., Crezee H; Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands., van Noorden CJF; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.; Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia. |
| Abstrakt: |
Mutations in the isocitrate dehydrogenase 1 (IDH1MUT) gene occur in various types of malignancies, including ~60% of chondrosarcomas, ~30% of intrahepatic cholangiocarcinomas and >80% of low-grade gliomas. IDH1MUT 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 IDH1MUT 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 IDH1MUT 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 IDH1MUT cancer cells compared to IDH1 wild-type cells. This vulnerability was abolished by the IDH1MUT inhibitor AGI-5198 and was further increased by the PARPi. In conclusion, our study shows that IDH1MUT 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 IDH1MUT chondrosarcoma of the extremities. |
