2. Academic Validation
  3. Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198

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

Affiliations

  • 1 Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. r.j.molenaar@amc.nl.
  • 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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