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Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer

Author

Listed:
  • Mohammad Asim

    (University of Cambridge
    University of Surrey)

  • Firas Tarish

    (Karolinska Institutet
    Central Hospital)

  • Heather I. Zecchini

    (University of Cambridge)

  • Kumar Sanjiv

    (Karolinska Institutet)

  • Eleni Gelali

    (Karolinska Institutet)

  • Charles E. Massie

    (University of Cambridge)

  • Ajoeb Baridi

    (University of Cambridge)

  • Anne Y. Warren

    (Addenbrooke’s Cambridge University Hospital)

  • Wanfeng Zhao

    (Addenbrooke’s Cambridge University Hospital)

  • Christoph Ogris

    (Karolinska Institutet)

  • Leigh-Anne McDuffus

    (University of Cambridge)

  • Patrice Mascalchi

    (University of Cambridge)

  • Greg Shaw

    (University of Cambridge)

  • Harveer Dev

    (University of Cambridge)

  • Karan Wadhwa

    (University of Cambridge)

  • Paul Wijnhoven

    (University of Cambridge)

  • Josep V. Forment

    (University of Cambridge)

  • Scott R. Lyons

    (University of Cambridge)

  • Andy G. Lynch

    (University of Cambridge)

  • Cormac O’Neill

    (University of Cambridge)

  • Vincent R. Zecchini

    (University of Cambridge)

  • Paul S. Rennie

    (University of British Columbia)

  • Aria Baniahmad

    (Jena University Hospital)

  • Simon Tavaré

    (University of Cambridge)

  • Ian G. Mills

    (University of Oslo
    Queen’s University)

  • Yaron Galanty

    (University of Cambridge)

  • Nicola Crosetto

    (Karolinska Institutet)

  • Niklas Schultz

    (Karolinska Institutet)

  • David Neal

    (University of Cambridge
    University of Oxford, John Radcliffe Hospital)

  • Thomas Helleday

    (Karolinska Institutet)

Abstract

Emerging data demonstrate homologous recombination (HR) defects in castration-resistant prostate cancers, rendering these tumours sensitive to PARP inhibition. Here we demonstrate a direct requirement for the androgen receptor (AR) to maintain HR gene expression and HR activity in prostate cancer. We show that PARP-mediated repair pathways are upregulated in prostate cancer following androgen-deprivation therapy (ADT). Furthermore, upregulation of PARP activity is essential for the survival of prostate cancer cells and we demonstrate a synthetic lethality between ADT and PARP inhibition in vivo. Our data suggest that ADT can functionally impair HR prior to the development of castration resistance and that, this potentially could be exploited therapeutically using PARP inhibitors in combination with androgen-deprivation therapy upfront in advanced or high-risk prostate cancer.

Suggested Citation

  • Mohammad Asim & Firas Tarish & Heather I. Zecchini & Kumar Sanjiv & Eleni Gelali & Charles E. Massie & Ajoeb Baridi & Anne Y. Warren & Wanfeng Zhao & Christoph Ogris & Leigh-Anne McDuffus & Patrice Ma, 2017. "Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00393-y
    DOI: 10.1038/s41467-017-00393-y
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