Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer
Nat Commun. 2017-08-29; 8(1):
DOI: 10.1038/s41467-017-00393-y
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1. 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.
Asim M(1)(2), Tarish F(3)(4), Zecchini HI(5), Sanjiv K(3), Gelali E(3), Massie
CE(5), Baridi A(5), Warren AY(6), Zhao W(6), Ogris C(3), McDuffus LA(5),
Mascalchi P(5), Shaw G(5), Dev H(5), Wadhwa K(5), Wijnhoven P(7), Forment JV(7),
Lyons SR(5), Lynch AG(5), O’Neill C(5), Zecchini VR(5), Rennie PS(8), Baniahmad
A(9), Tavaré S(5), Mills IG(10)(11), Galanty Y(7), Crosetto N(3), Schultz N(3),
Neal D(12)(13), Helleday T(14).
Author information:
(1)Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre,
Cambridge, CB2 0RE, UK. .
(2)Department of Clinical and Experimental Medicine, University of Surrey,
Guildford, GU2 7WG, 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. .
(13)Nuffield Department of Surgery, University of Oxford, John Radcliffe
Hospital, Headley Way, Headington, Oxford, OX3 9DU, 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. .
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.
DOI: 10.1038/s41467-017-00393-y
PMCID: PMC5575038
PMID: 28851861 [Indexed for MEDLINE]