2. Academic Validation
  3. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity

2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity

  • Sci Transl Med. 2017 Feb 1;9(375):eaal2463. doi: 10.1126/scitranslmed.aal2463.
Parker L Sulkowski 1 2,  Christopher D Corso 1,  Nathaniel D Robinson 1,  Susan E Scanlon 1 3,  Karin R Purshouse 1,  Hanwen Bai 2,  Yanfeng Liu 1,  Ranjini K Sundaram 1,  Denise C Hegan 1,  Nathan R Fons 1 3,  Gregory A Breuer 1 3,  Yuanbin Song 4,  Ketu Mishra-Gorur 5,  Henk M De Feyter 6,  Robin A de Graaf 6,  Yulia V Surovtseva 7,  Maureen Kachman 8,  Stephanie Halene 4,  Murat Günel 2 5,  Peter M Glazer 9 2,  Ranjit S Bindra 9 3
Affiliations

Affiliations

  • 1 Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 2 Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 3 Department of Experimental Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 4 Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 5 Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 6 Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 7 Yale Center for Molecular Discovery, West Haven, CT 06516, USA.
  • 8 Michigan Regional Comprehensive Metabolomics Resource Core, National Institute of Environmental Health Sciences (NIEHS) Children's Health Exposure Analysis Resource for Metabolomics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • 9 Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. ranjit.bindra@yale.edu peter.glazer@yale.edu.
PMID: 28148839 DOI: 10.1126/scitranslmed.aal2463
Abstract

2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors. This "BRCAness" phenotype of IDH mutant cells can be completely reversed by treatment with small-molecule inhibitors of the mutant IDH1 Enzyme, and conversely, it can be entirely recapitulated by treatment with either of the 2HG enantiomers in cells with intact IDH1/2 proteins. We demonstrate mutant IDH1-dependent PARP Inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in culture and genetically matched tumor xenografts in vivo. These findings provide the basis for a possible therapeutic strategy exploiting the biological consequences of mutant IDH, rather than attempting to block 2HG production, by targeting the 2HG-dependent HR deficiency with PARP inhibition. Furthermore, our results uncover an unexpected link between oncometabolites, altered DNA repair, and genetic instability.

Figures
Products