2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity.
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.
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.|Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
Parker L
PL
Sulkowski
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Christopher D
CD
Corso
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Nathaniel D
ND
Robinson
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.|Department of Experimental Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
Susan E
SE
Scanlon
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Karin R
KR
Purshouse
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
Hanwen
H
Bai
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Yanfeng
Y
Liu
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Ranjini K
RK
Sundaram
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Denise C
DC
Hegan
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.|Department of Experimental Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
Nathan R
NR
Fons
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.|Department of Experimental Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
Gregory A
GA
Breuer
Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Yuanbin
Y
Song
Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, USA.
Ketu
K
Mishra-Gorur
Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06520, USA.
Henk M
HM
De Feyter
Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06520, USA.
Robin A
RA
de Graaf
Yale Center for Molecular Discovery, West Haven, CT 06516, USA.
Yulia V
YV
Surovtseva
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.
Maureen
M
Kachman
Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Stephanie
S
Halene
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.|Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, USA.
Murat
M
Günel
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. ranjit.bindra@yale.edu peter.glazer@yale.edu.|Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
Peter M
PM
Glazer
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. ranjit.bindra@yale.edu peter.glazer@yale.edu.|Department of Experimental Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
Ranjit S
RS
Bindra
D000818:Animals; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics; D005977:Glutarates / Q000494:pharmacology*; D059765:Homologous Recombination; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000494:pharmacology; D008819:Mice, Nude; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D005977:Glutarates; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human