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

Parker L. Sulkowski; Christopher D. Corso; Nathaniel D. Robinson; Susan E. Scanlon; Karin R. Purshouse; Hanwen Bai; Yanfeng Liu; Ranjini K. Sundaram; Denise C. Hegan; Nathan R. Fons; Gregory A. Breuer; Yuanbin Song; Ketu Mishra-Gorur; Henk M. De Feyter; Robin A. de Graaf; Yulia V. Surovtseva; Maureen Kachman; Stephanie Halene; Murat Günel; Peter M. Glazer; Ranjit S. Bindra

doi:10.1126/scitranslmed.aal2463

Research ArticleCancer

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

Parker L. Sulkowski¹,²,*,
Christopher D. Corso¹,*,
Nathaniel D. Robinson¹,
Susan E. Scanlon¹,³,
Karin R. Purshouse¹,
Hanwen Bai²,
Yanfeng Liu¹,
Ranjini K. Sundaram¹,
Denise C. Hegan¹,
Nathan R. Fons¹,³,
Gregory A. Breuer¹,³,
Yuanbin Song⁴,
Ketu Mishra-Gorur⁵,
Henk M. De Feyter⁶,
Robin A. de Graaf⁶,
Yulia V. Surovtseva⁷,
Maureen Kachman⁸,
Stephanie Halene⁴,
Murat Günel²,⁵,
Peter M. Glazer¹,²,† and
Ranjit S. Bindra¹,³,†

¹Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
²Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
³Department of Experimental Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
⁴Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
⁵Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, USA.
⁶Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06520, USA.
⁷Yale Center for Molecular Discovery, West Haven, CT 06516, USA.
⁸Michigan 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.

↵†Corresponding author. Email: ranjit.bindra{at}yale.edu (R.S.B.); peter.glazer{at}yale.edu (P.M.G.)

↵* These authors contributed equally to this work.

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Science Translational Medicine 01 Feb 2017:
Vol. 9, Issue 375, eaal2463
DOI: 10.1126/scitranslmed.aal2463

Parker L. Sulkowski

1Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.

2Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.

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Christopher D. Corso

1Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.

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Nathaniel D. Robinson

1Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.

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Susan E. Scanlon

1Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.

3Department of Experimental Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.

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Karin R. Purshouse

1Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.

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Hanwen Bai

2Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.

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Yanfeng Liu

1Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.

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Ranjini K. Sundaram

1Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.

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Denise C. Hegan

1Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.

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Nathan R. Fons

1Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.

3Department of Experimental Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.

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Gregory A. Breuer

1Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.

3Department of Experimental Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.

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Yuanbin Song

4Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.

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Ketu Mishra-Gorur

5Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, USA.

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Henk M. De Feyter

6Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06520, USA.

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Robin A. de Graaf

6Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06520, USA.

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Yulia V. Surovtseva

7Yale Center for Molecular Discovery, West Haven, CT 06516, USA.

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Maureen Kachman

8Michigan 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.

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Stephanie Halene

4Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.

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Murat Günel

2Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.

5Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, USA.

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Peter M. Glazer

1Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.

2Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.

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For correspondence: ranjit.bindra@yale.edu peter.glazer@yale.edu

Ranjit S. Bindra

1Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.

3Department of Experimental Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.

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For correspondence: ranjit.bindra@yale.edu peter.glazer@yale.edu

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The oncometabolite 2-hydroxyglutarate renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.

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

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