title: Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198.
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.
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. r.j.molenaar@amc.nl.
authors.forename: Remco J
authors.initials: RJ
authors.lastname: Molenaar
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Dennis
authors.initials: D
authors.lastname: Botman
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Myrthe A
authors.initials: MA
authors.lastname: Smits
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Vashendriya V
authors.initials: VV
authors.lastname: Hira
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Sanne A
authors.initials: SA
authors.lastname: van Lith
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Stap
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Henneman
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Khurshed
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Krissie
authors.initials: K
authors.lastname: Lenting
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Adri N
authors.initials: AN
authors.lastname: Mul
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Dionysia
authors.initials: D
authors.lastname: Dimitrakopoulou
authors.affiliation: Department of Otorhinolaryngology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Cornelis M
authors.initials: CM
authors.lastname: van Drunen
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Ron A
authors.initials: RA
authors.lastname: Hoebe
authors.affiliation: Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Tomas
authors.initials: T
authors.lastname: Radivoyevitch
authors.affiliation: Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Johanna W
authors.initials: JW
authors.lastname: Wilmink
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.affiliation: Department of Neurosurgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. Department of Neurosurgery, VU Medical Center, Amsterdam, the Netherlands.
authors.forename: W Peter
authors.initials: WP
authors.lastname: Vandertop
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: William P
authors.initials: WP
authors.lastname: Leenders
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Fonnet E
authors.initials: FE
authors.lastname: Bleeker
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: van Noorden
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D044482:Benzeneacetamides / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy / Q000009:adverse effects; D019175:DNA Methylation / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D055879:Gene Knock-In Techniques; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D009154:Mutation; D009249:NADP / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D011836:Radiation Tolerance / Q000187:drug effects*
chemical_list: C581156:AGI-5198; D000970:Antineoplastic Agents; D044482:Benzeneacetamides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009249:NADP; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human