Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198

  • Cancer Res. 2015 Nov 15;75(22):4790-802. doi: 10.1158/0008-5472.CAN-14-3603.
Remco J Molenaar  1 ,  Dennis Botman  2 ,  Myrthe A Smits  2 ,  Vashendriya V Hira  2 ,  Sanne A van Lith  3 ,  Jan Stap  2 ,  Peter Henneman  4 ,  Mohammed Khurshed  2 ,  Krissie Lenting  3 ,  Adri N Mul  4 ,  Dionysia Dimitrakopoulou  2 ,  Cornelis M van Drunen  5 ,  Ron A Hoebe  2 ,  Tomas Radivoyevitch  6 ,  Johanna W Wilmink  7 ,  Jaroslaw P Maciejewski  8 ,  W Peter Vandertop  9 ,  William P Leenders  3 ,  Fonnet E Bleeker  4 ,  Cornelis J van Noorden  2
Affiliations
  • 1. Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. [email protected].
  • 2. Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
  • 3. Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 4. Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
  • 5. Department of Otorhinolaryngology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
  • 6. Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
  • 7. Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
  • 8. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
  • 9. Department of Neurosurgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. Department of Neurosurgery, VU Medical Center, Amsterdam, the Netherlands.
PMID: 26363012 DOI: 10.1158/0008-5472.CAN-14-3603
Abstract

Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human Cancer to IDH1(R132H), a structural alteration that leads to catalysis of α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate. In this study, we present evidence that small-molecule inhibitors of IDH1(R132H) that are being developed for Cancer therapy may pose risks with coadministration of radiotherapy. Cancer cells heterozygous for the IDH1(R132H) mutation exhibited less IDH-mediated production of NADPH, such that after exposure to ionizing radiation (IR), there were higher levels of Reactive Oxygen Species, DNA double-strand breaks, and cell death compared with IDH1 wild-type cells. These effects were reversed by the IDH1(R132H) inhibitor AGI-5198. Exposure of IDH1 wild-type cells to D-2-hydroxyglutarate was sufficient to reduce IDH-mediated NADPH production and increase IR sensitivity. Mechanistic investigations revealed that the radiosensitivity of heterozygous cells was independent of the well-described DNA hypermethylation phenotype in IDH1-mutated cancers. Thus, our results argue that altered oxidative stress responses are a plausible mechanism to understand the radiosensitivity of IDH1-mutated Cancer cells. Further, they offer an explanation for the relatively longer survival of patients with IDH1-mutated tumors, and they imply that administration of IDH1(R132H) inhibitors in these patients may limit irradiation efficacy in this setting.

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