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
  • 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. [email protected] [email protected].
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.

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