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

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 Mascalchi, Greg Shaw, Harveer Dev, Karan Wadhwa, Paul Wijnhoven, Josep V. Forment, Scott R. Lyons, Andy G. Lynch, Cormac O’Neill, Vincent R. Zecchini, Paul S. Rennie, Aria Baniahmad, Simon Tavaré, Ian G. Mills, Yaron Galanty, Nicola Crosetto, Niklas Schultz, David Neal () and Thomas Helleday ()
Additional contact information
Mohammad Asim: University of Cambridge
Firas Tarish: Karolinska Institutet
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
Yaron Galanty: University of Cambridge
Nicola Crosetto: Karolinska Institutet
Niklas Schultz: Karolinska Institutet
David Neal: University of Cambridge
Thomas Helleday: Karolinska Institutet

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00393-y

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