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Nat Commun. 2017 Aug 29;8(1):374. doi: 10.1038/s41467-017-00393-y.

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

Author information

1
Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK. mohammad.asim@cruk.cam.ac.uk.
2
Department of Clinical and Experimental Medicine, University of Surrey, Guildford, GU2 7WG, UK. mohammad.asim@cruk.cam.ac.uk.
3
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21, Stockholm, Sweden.
4
Department of Urology, Central Hospital, 721 89, Västerås, Sweden.
5
Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK.
6
Department of Pathology, Addenbrooke's Cambridge University Hospital, Cambridge, CB2 0QQ, UK.
7
The Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, UK.
8
The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada, V6H 3Z6.
9
Institute of Human Genetics, Jena University Hospital, 07743, Jena, Germany.
10
Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, University of Oslo, 0318, Oslo, Norway.
11
Prostate Cancer UK/Movember Centre of Excellence, Queen's University, Belfast, BT9 7AE, UK.
12
Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK. david.neal@nds.ox.ac.uk.
13
Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK. david.neal@nds.ox.ac.uk.
14
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21, Stockholm, Sweden. Thomas.helleday@scilifelab.se.

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.Tumours with homologous recombination (HR) defects become sensitive to PARPi. Here, the authors show that androgen receptor (AR) regulates HR and AR inhibition activates the PARP pathway in vivo, thus inhibition of both AR and PARP is required for effective treatment of high risk prostate cancer.

PMID:
28851861
PMCID:
PMC5575038
DOI:
10.1038/s41467-017-00393-y
[Indexed for MEDLINE]
Free PMC Article

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