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Target 2HG or not 2HG, that is the question

Mutations in isocitrate dehydrogenase 1 and 2, which result in overproduction of 2-hydroxyglutarate (2HG), are observed in multiple tumor types, including gliomas and acute myelogenous leukemia. An additional form of 2HG is produced under hypoxia, which is also frequent in tumors. 2HG is considered to be an oncometabolite, or a metabolite that promotes carcinogenesis, and inhibitors of mutant isocitrate dehydrogenase are in development to target this process. However, Sulkowski et al. found that it may be possible to take advantage of 2HG overproduction instead. The authors discovered that 2HG overproduction impairs homologous recombination used in DNA repair and sensitizes cancer cells to treatment with PARP inhibitors, another class of cancer drugs that are already in clinical use.

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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Supplementary Material

Summary

Materials and Methods
Fig. S1. Establishment and characterization of IDH mutant and WT cell models.
Fig. S2. Characterization of the DNA DSB repair defect in IDH mutant cells.
Fig. S3. Cell growth and viability assays in response to DNA repair and DNA damage response inhibitors.
Fig. S4. Increased sensitivity of IDH mutant cells to PARP inhibitors alone and in combination with cisplatin.
Fig. S5. Additional characterization of the impact of 2HG on DNA DSB repair.
Fig. S6. Manipulation of IDH and L2HGDH by siRNAs and impact on DNA DSB repair.
Fig. S7. Rescue of 2HG-induced HR defect by αKG, role of KDM4A/B in DNA repair regulation by mutant IDH1, and lack of correlation with NAD+ concentration.
Fig. S8. Additional glioma cell and xenograft data.
Table S1. STR profile of IDH WT parental HeLa cells.
Table S2. STR profile of IDH1 R132H/+ HeLa cell subclone.
Table S3. List of siRNAs targeting αKG-dependent dioxygenases and selected DNA repair proteins.
Table S4. Surviving fraction of 50% values for clonogenic survival assays.
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Information & Authors

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Published In

Science Translational Medicine
Volume 9 | Issue 375
February 2017

Submission history

Received: 19 October 2016
Accepted: 23 December 2016

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Acknowledgments

We thank A. von Deimling for providing us with the HGDH enzyme; T. Taniguchi for providing us with the PEO1, PEO4, and dPEO1 C4-2 cells; R. Majeti for the THP1 cells; and T. Chan for providing us with immortalized astrocytes. We apologize to those whose work we cannot list because of the reference limitations for a publication in this journal. Funding: This work was supported by the NIH (R01ES005775, R01CA168733, and R01 CA177719 to P.M.G.), by the American Cancer Society (research scholar grant to R.S.B.), and by the Connecticut Department of Public Health (RFP 2014-0135 to S.H.). N.D.R. is a Howard Hughes Medical Institute Medical Research Fellow. S.E.S. was supported by the NIH Medical Scientist Program Training grant T32GM007205 and NIH National Institute of General Medical Sciences training grant T32GM007223. The work on this paper used Metabolomics Core services supported by grant U24 DK097153 of NIH Common Funds Project to the University of Michigan. Author contributions: P.L.S. and C.D.C. contributed to the experiments, scientific hypotheses, data analysis, and compiling of the manuscript. N.D.R., S.E.S., K.R.P., Y.L., R.K.S, D.C.H., N.R.F., Y.S., K.M.-G., H.M.D.F., R.A.d.G., Y.V.S., and M.K. contributed to the experiments. M.G., H.B., and G.A.B. contributed to the data analysis. S.H., P.M.G., and R.S.B. designed the experiments. P.L.S., C.D.C., P.M.G., and R.S.B. wrote the manuscript. Competing interests: R.S.B. and P.M.G. are inventors on the U.S. patent application no. 62/344,678 submitted by Yale University, which covers compositions and methods for targeting and treating HR-deficient tumors. Data and materials availability: The in-house software written in MATLAB (MathWorks) is available for download by directly contacting R.A.d.G. (http://mrrc.yale.edu/faculty/robin_degraaf.profile). For all other reagents and data requests, please contact R.S.B. ([email protected]).

Authors

Affiliations

Parker L. Sulkowski*
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.
Christopher D. Corso*
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Nathaniel D. Robinson
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Susan E. Scanlon
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.
Karin R. Purshouse
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Hanwen Bai
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
Yanfeng Liu
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Ranjini K. Sundaram
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Denise C. Hegan
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Nathan R. 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. Breuer
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.
Yuanbin Song
Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Ketu Mishra-Gorur
Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, USA.
Henk M. De Feyter
Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06520, USA.
Robin A. de Graaf
Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06520, USA.
Yulia V. Surovtseva
Yale Center for Molecular Discovery, West Haven, CT 06516, USA.
Maureen Kachman
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.
Stephanie Halene
Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Murat Günel
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.
Peter M. Glazer [email protected]
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.
Ranjit S. Bindra [email protected]
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.

Notes

*
These authors contributed equally to this work.
Corresponding author. Email: [email protected] (R.S.B.); [email protected] (P.M.G.)

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