Skip to content

Research at St Andrews

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

Research output: Contribution to journalArticle

DOI

Open Access permissions

Open

Author(s)

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 & 10 others Vincent R Zecchini, Paul S Rennie, Aria Baniahmad, Simon Tavaré, Ian G Mills, Yaron Galanty, Nicola Crosetto, Niklas Schultz, David Neal, Thomas Helleday

School/Research organisations

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.

Close

Details

Original languageEnglish
Article number374
Number of pages10
JournalNature Communications
Volume8
DOIs
StatePublished - 29 Aug 2017

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data

    Camacho, N. , Van Loo, P. , Edwards, S. , Kay, J. D. , Matthews, L. , Haase, K. , Clark, J. , Dennis, N. , Thomas, S. , Kremeyer, B. , Zamora, J. , Butler, A. P. , Gundem, G. , Merson, S. , Luxton, H. , Hawkins, S. , Ghori, M. , Marsden, L. , Lambert, A. , Karaszi, K. & 37 others Pelvender, G., Massie, C. E., Kote-Jarai, Z. S., Raine, K., Jones, D., Howat, W. J., Hazell, S., Livni, N., Fisher, C., Ogden, C., Kumar, P., Thompson, A., Nicol, D., Mayer, E., Dudderidge, T., Yu, Y., Zhang, H., Shah, N. C., Gnanapragasam, V. J., Group, T. C. R. U. K-I. C. G. C. P., Isaacs, W., Visakorpi, T., Hamdy, F., Berney, D., Verrill, C., Warren, A. Y., Wedge, D. C., Lynch, A. G., Foster, C. S., Lu, Y. J., Bova, G. S., Whitaker, H. C., McDermott, U., Neal, D. E., Eeles, R., Cooper, C. S. & Brewer, D. S. 25 Sep 2017 In : PLoS Genetics. 13, 9, e1007001

    Research output: Contribution to journalArticle

  2. The role of TET-mediated DNA hydroxymethylation in prostate cancer

    Smeets, E., Lynch, A. G., Prekovic, S., Van den Broeck, T., Moris, L., Helsen, C., Joniau, S., Claessens, F. & Massie, C. E. 1 Sep 2017 In : Molecular and Cellular Endocrinology. In press

    Research output: Contribution to journalArticle

  3. Genomic evolution of breast cancer metastasis and relapse

    Yates, L. R. , Knappskog, S. , Wedge, D. , Farmery, J. H. R. , Gonzalez, S. , Martincorena, I. , Alexandrov, L. B. , Van Loo, P. , Haugland, H. K. , Lilleng, P. K. , Gundem, G. , Gerstung, M. , Pappaemmanuil, E. , Gazinska, P. , Bhosle, S. G. , Jones, D. , Raine, K. , Mudie, L. , Latimer, C. , Sawyer, E. & 10 others Desmedt, C., Sotiriou, C., Stratton, M. R., Sieuwerts, A. M., Lynch, A. G., Martens, J. W., Richardson, A. L., Tutt, A., Lønning, P. E. & Campbell, P. J. 14 Aug 2017 In : Cancer Cell. 32, 2, p. 169-184 e7

    Research output: Contribution to journalArticle

  4. New model for estimating glomerular filtration rate in patients with cancer

    Janowitz, T., Williams, E. H., Marshall, A., Ainsworth, N., Thomas, P. B., Sammut, S. J., Shepherd, S., White, J., Mark, P. B., Lynch, A. G., Jodrell, D. I., Tavaré, S. & Earl, H. 7 Jul 2017 In : Journal of Clinical Oncology. Online First, 10 p.

    Research output: Contribution to journalArticle

  5. A comparative analysis of whole genome sequencing of esophageal adenocarcinoma pre- and post-chemotherapy

    Noorani, A., Bornschein, J., Lynch, A. G., Secrier, M., Achilleos, A., Eldridge, M., Bower, L., Weaver, J. M. J., Crawte, J., Ong, C-A., Shannon, N., MacRae, S., Grehan, N., Nutzinger, B., O'Donovan, M., Hardwick, R., Tavaré, S., Fitzgerald, R. C. & on behalf of the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium 1 Jun 2017 In : Genome Research. 27, 6, p. 902-912 11 p.

    Research output: Contribution to journalArticle

Related by journal

  1. Taking the pulse of Mars via dating of a plume-fed volcano

    Cohen, B. E., Mark, D. F., Cassata, W. S., Lee, M. R., Tomkinson, T. & Smith, C. L. 3 Oct 2017 In : Nature Communications. 8, 9 p., 640

    Research output: Contribution to journalArticle

  2. Observation of hybrid Tamm-plasmon exciton-polaritons with GaAs quantum wells and a MoSe2 monolayer

    Wurdack, M., Lundt, N., Klaas, M., Baumann, V., Kavokin, A., Höfling, S. & Schneider, C. 15 Aug 2017 In : Nature Communications. 8, 6 p., 259

    Research output: Contribution to journalArticle

  3. Living GenoChemetics by hyphenating synthetic biology and synthetic chemistry in vivo

    Sharma, S. V., Tong, X., Pubill-Ulldemolins, C., Cartmell, C., Bogosyan, E. J. A., Rackham, E. J., Marelli, E., Hamed, R. B. & Goss, R. J. M. 9 Aug 2017 In : Nature Communications. 8, 10 p., 229

    Research output: Contribution to journalArticle

  4. Charge carrier localised in zero-dimensional (CH3NH3)3Bi219 clusters

    Ni, C., Hedley, G. J., Payne, J. L., Svrcek, V., McDonald, C., Jagadamma, L. K., Edwards, P., Martin, R., Jain, G., Carolan, D., Mariotti, D., Maguire, P., Samuel, I. D. W. & Irvine, J. T. S. 1 Aug 2017 In : Nature Communications. 8, 7 p., 170

    Research output: Contribution to journalArticle

ID: 251034661