Skip to content

Research at St Andrews

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

Research output: Research - peer-reviewArticle

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. Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal

    Mitchell, T. J. , Turajlic, S. , Rowan, A. , Nicol, D. , Farmery, J. H. R. , O’Brien, T. , Martincorena, I. , Tarpey, P. , Angelopoulos, N. , Yates, L. R. , Butler, A. P. , Raine, K. , Stewart, G. D. , Challacombe, B. , Fernando, A. , Lopez, J. I. , Hazell, S. , Chandra, A. , Chowdhury, S. , Rudman, S. & 27 others Soultati, A., Stamp, G., Fotiadis, N., Pickering, L., Au, L., Spain, L., Lynch, J., Stares, M., Teague, J., Maura, F., Wedge, D. C., Horswell, S., Chambers, T., Litchfield, K., Xu, H., Stewart, A., Elaidi, R., Oudard, S., McGranahan, N., Csabai, I., Gore, M., Futreal, P. A., Larkin, J., Lynch, A. G., Szallasi, Z., Swanton, C. & Campbell, P. J. 19 Apr 2018 In : Cell. 173, 3, p. 611-623 13 p., e17

    Research output: Research - peer-reviewArticle

  2. Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

    Wedge, D. C. , Gundem, G. , Mitchell, T. , Woodstock, D. J. , Martincorena, I. , Ghori, M. , Zamora, J. , Butler, A. , Whitaker, H. , Kote-Jarai, Z. , Alexandrov, L. B. , Van Loo, P. , Massie, C. E. , Dentro, S. , Warren, A. Y. , Verrill, C. , Berney, D. M. , Dennis, N. , Merson, S. , Hawkins, S. & 65 others Howat, W., Lu, Y-J., Lambert, A., Kay, J., Kremeyer, B., Karaszi, K., Luxton, H., Camacho, N., Marsden, L., Edwards, S., Matthews, L., Bo, V., Leongamornlert, D., McLaren, S., Ng, A., Yu, Y., Zhang, H., Dadaev, T., Thomas, S., Easton, D. F., Ahmed, M., Bancroft, E., Fisher, C., Livni, N., Nicol, D., Tavaré, S., Gill, P., Greenman, C., Khoo, V., Van As, N., Kumar, P., Ogden, C., Cahill, D., Thompson, A., Meyer, E., Rowe, E., Dudderidge, T., Jones, D., Menzies, A., Stebbings, L., Teague, J., Hazell, S., Corbishley, C., CAMCAP study group, de Bono, J., Attard, G., Isaacs, W., Visakorpi, T., Fraser, M., Boutros, P. C., Bristow, R. G., Workman, P., Sander, C., The TCGA consortium, Hamdy, F. C., Futreal, A., McDermott, U., Al-Lazikani, B., Lynch, A., Bova, G. S., Foster, C. S., Brewer, D. S., Neal, D. E., Cooper, C. S. & Eeles, R. A. 16 Apr 2018 In : Nature Genetics. 16 p.

    Research output: Research - peer-reviewArticle

  3. 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. 15 Feb 2018 In : Molecular and Cellular Endocrinology. 462, A, p. 41-55

    Research output: Research - peer-reviewReview article

  4. Telomerecat: a ploidy-agnostic method for estimating telomere length from whole genome sequencing data

    Farmery, J., Smith, M., NIHR BioResource - Rare Diseases & Lynch, A. 22 Jan 2018 In : Scientific Reports. 8, 17 p., 1300

    Research output: Research - peer-reviewArticle

  5. 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: Research - peer-reviewArticle

Related by journal

  1. Crossover from lattice to plasmonic polarons of a spin-polarised electron gas in ferromagnetic EuO

    Riley, J. M., Caruso, F., Verdi, C., Duffy, L., Watson, M. D., Bawden, L., Volckaert, K., van der Laan, G., Hesjedal, T., Hoesch, M., Giustino, F. & King, P. D. 13 Jun 2018 In : Nature Communications. 9, 8 p., 2305

    Research output: Research - peer-reviewArticle

  2. Innovation and cumulative culture through tweaks and leaps in online programming contests

    Miu, E., Gulley, N., Laland, K. N. & Rendell, L. 13 Jun 2018 In : Nature Communications. 9, 8 p., 2321

    Research output: Research - peer-reviewArticle

  3. Flexible and ultra-lightweight polymer membrane lasers

    Karl, M., Glackin, J. M. E., Schubert, M., Kronenberg, N. M., Turnbull, G. A., Samuel, I. D. W. & Gather, M. C. 1 May 2018 In : Nature Communications. 9, 7 p., 1525

    Research output: Research - peer-reviewArticle

  4. Reflection from a free carrier front via an intraband indirect photonic transition

    Gaafar, M. A., Jalas, D., O’Faolain, L., Li, J., Krauss, T. F., Petrov, A. Y. & Eich, M. 13 Apr 2018 In : Nature Communications. 9, 10 p., 1447

    Research output: Research - peer-reviewArticle

  5. A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage

    Ladds, M. J. G. W. , van Leeuwen, I. M. M. , Drummond, C. J. , Chu, S. , Healy, A. R. , Popova, G. , Pastor-Fernández, A. , Mollick, T. , Darekar, S. , Sedimbi, S. K. , Nekulova, M. , Sachweh, M. C. C. , Campbell, J. , Higgins, M. , Tuck, C. , Popa, M. , Safont, M. M. , Gelebart, P. , Fandalyuk, Z. , Thompson, A. M. & 26 others Svensson, R., Gustavsson, A-L., Johansson, L., Färnegårdh, K., Yngve, U., Saleh, A., Haraldsson, M., D'Hollander, A. C. A., Franco, M., Zhao, Y., Håkansson, M., Walse, B., Larsson, K., Peat, E. M., Pelechano, V., Lunec, J., Vojtesek, B., Carmena, M., Earnshaw, W. C., McCarthy, A. R., Westwood, N. J., Arsenian-Henriksson, M., Lane, D. P., Bhatia, R., McCormack, E. & Laín, S. 16 Mar 2018 In : Nature Communications. 9, 1107

    Research output: Research - peer-reviewArticle

Related by journal

  1. Nature Communications (Journal)

    Gardner, A. (Reviewer)
    Feb 2018

    Activity: Publication peer-review and editorial workPeer review of manuscripts

ID: 251034661