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

• Published in: Science translational medicine Vol. 9; no. 375
• Main Authors: Sulkowski, Parker L, Corso, Christopher D, Robinson, Nathaniel D, Scanlon, Susan E, Purshouse, Karin R, Bai, Hanwen, Liu, Yanfeng, Sundaram, Ranjini K, Hegan, Denise C, Fons, Nathan R, Breuer, Gregory A, Song, Yuanbin, Mishra-Gorur, Ketu, De Feyter, Henk M, de Graaf, Robin A, Surovtseva, Yulia V, Kachman, Maureen, Halene, Stephanie, Günel, Murat, Glazer, Peter M, Bindra, Ranjit S
• Format: Journal Article
• Language: English
• Published: United States 01.02.2017
• Subjects: Animals; Cell Line, Tumor; DNA Breaks, Double-Stranded; DNA Repair; Female; Glioma - drug therapy; Glioma - genetics; Glutarates - pharmacology; Homologous Recombination; Humans; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - pharmacology; Mice, Nude; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Xenograft Model Antitumor Assays
• DOI: 10.1126/scitranslmed.aal2463

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.