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Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors

  1. Ana M. Mendes-Pereira1,
  2. Sarah A. Martin1,2,
  3. Rachel Brough1,2,
  4. Afshan McCarthy1,
  5. Jessica R. Taylor1,
  6. Jung-Sik Kim3,
  7. Todd Waldman3,
  8. Christopher J. Lord1,*,
  9. Alan Ashworth1,2,*

Article first published online: 16 SEP 2009

DOI: 10.1002/emmm.200900041

Issue

EMBO Molecular Medicine

EMBO Molecular Medicine

Volume 1, Issue 6-7, pages 315–322, September/October 2009

Additional Information

How to Cite

Mendes-Pereira, A. M., Martin, S. A., Brough, R., McCarthy, A., Taylor, J. R., Kim, J.-S., Waldman, T., Lord, C. J. and Ashworth, A. (2009), Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med, 1: 315–322. doi: 10.1002/emmm.200900041

Author Information

  1. 1

    The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK

  2. 2

    CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK

  3. 3

    Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, District of Columbia, USA

*Tel: +44 0207 1535334; Fax: +44 0207 3523299

Publication History

  1. Issue published online: 28 SEP 2009
  2. Article first published online: 16 SEP 2009
  3. Manuscript Accepted: 31 JUL 2009
  4. Manuscript Revised: 24 JUL 2009
  5. Manuscript Received: 6 APR 2009

Funded by

  • Breakthrough Breast Cancer
  • Cancer Research UK
  • NHS

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Keywords:

  • PTEN;
  • PARP inhibitor;
  • homologous recombination

Abstract

The tumour suppressor gene, phosphatase and tensin homolog (PTEN), is one of the most commonly mutated genes in human cancers. Recent evidence suggests that PTEN is important for the maintenance of genome stability. Here, we show that PTEN deficiency causes a homologous recombination (HR) defect in human tumour cells. The HR deficiency caused by PTEN deficiency, sensitizes tumour cells to potent inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), both in vitro and in vivo. PARP inhibitors are now showing considerable promise in the clinic, specifically in patients with mutations in either of the breast cancer susceptibility genes BRCA1 or BRCA2. The data we present here now suggests that the clinical assessment of PARP inhibitors should be extended beyond those with BRCA mutations to a larger group of patients with PTEN mutant tumours.

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