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

Autor: Asim M; Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK. mohammad.asim@cruk.cam.ac.uk.; Department of Clinical and Experimental Medicine, University of Surrey, Guildford, GU2 7WG, UK. mohammad.asim@cruk.cam.ac.uk., Tarish F; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21, Stockholm, Sweden.; Department of Urology, Central Hospital, 721 89, Västerås, Sweden., Zecchini HI; Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK., Sanjiv K; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21, Stockholm, Sweden., Gelali E; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21, Stockholm, Sweden., Massie CE; Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK., Baridi A; Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK., Warren AY; Department of Pathology, Addenbrooke's Cambridge University Hospital, Cambridge, CB2 0QQ, UK., Zhao W; Department of Pathology, Addenbrooke's Cambridge University Hospital, Cambridge, CB2 0QQ, UK., Ogris C; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21, Stockholm, Sweden., McDuffus LA; Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK., Mascalchi P; Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK., Shaw G; Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK., Dev H; Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK., Wadhwa K; Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK., Wijnhoven P; The Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, UK., Forment JV; The Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, UK., Lyons SR; Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK., Lynch AG; Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK., O'Neill C; Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK., Zecchini VR; Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK., Rennie PS; The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada, V6H 3Z6., Baniahmad A; Institute of Human Genetics, Jena University Hospital, 07743, Jena, Germany., Tavaré S; Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK., Mills IG; Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, University of Oslo, 0318, Oslo, Norway.; Prostate Cancer UK/Movember Centre of Excellence, Queen's University, Belfast, BT9 7AE, UK., Galanty Y; The Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, UK., Crosetto N; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21, Stockholm, Sweden., Schultz N; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21, Stockholm, Sweden., Neal D; Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK. david.neal@nds.ox.ac.uk.; Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK. david.neal@nds.ox.ac.uk., Helleday T; 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.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2017 Aug 29; Vol. 8 (1), pp. 374. Date of Electronic Publication: 2017 Aug 29.
DOI: 10.1038/s41467-017-00393-y
Abstrakt: 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.
Databáze: MEDLINE