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

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Date
29/08/2017
Author
Asim, Mohammad
Tarish, Firas
Zecchini, Heather I
Sanjiv, Kumar
Gelali, Eleni
Massie, Charles E
Baridi, Ajoeb
Warren, Anne Y
Zhao, Wanfeng
Ogris, Christoph
McDuffus, Leigh-Anne
Mascalchi, Patrice
Shaw, Greg
Dev, Harveer
Wadhwa, Karan
Wijnhoven, Paul
Forment, Josep V
Lyons, Scott R
Lynch, Andy G
O'Neill, Cormac
Zecchini, Vincent R
Rennie, Paul S
Baniahmad, Aria
Tavaré, Simon
Mills, Ian G
Galanty, Yaron
Crosetto, Nicola
Schultz, Niklas
Neal, David
Helleday, Thomas
Keywords
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
NDAS
BDC
R2C
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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.
Citation
Asim , M , Tarish , F , Zecchini , H I , Sanjiv , K , Gelali , E , Massie , C E , Baridi , A , Warren , A Y , Zhao , W , Ogris , C , McDuffus , L-A , Mascalchi , P , Shaw , G , Dev , H , Wadhwa , K , Wijnhoven , P , Forment , J V , Lyons , S R , Lynch , A G , O'Neill , C , Zecchini , V R , Rennie , P S , Baniahmad , A , Tavaré , S , Mills , I G , Galanty , Y , Crosetto , N , Schultz , N , Neal , D & Helleday , T 2017 , ' Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer ' , Nature Communications , vol. 8 , 374 . https://doi.org/10.1038/s41467-017-00393-y
Publication
Nature Communications
Status
Peer reviewed
DOI
https://doi.org/10.1038/s41467-017-00393-y
ISSN
2041-1723
Type
Journal article
Rights
© 2017 The Authors. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Description
This study was supported by the National Cancer Research Institute (National Institute of Health Research (NIHR) Collaborative Study: ‘Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT)” (grant G0500966/75466). This work was funded by a Cancer Research UK program grant (D.N.), the Swedish Research Council (T.H.), AFA insurance (T.H.), Swedish Cancer Society (T.H.), the Swedish Pain Relief Foundation (T.H.), the Torsten and Ragnar Söderberg Foundation (T.H.), AstraZeneca (T.H.) Centre for Clinical Research (CKF) (F.T.), the Västmanland Research Foundation for Cancer in Vasteras (F.T.), the Henning and Ida Persson Research Foundation (F.T.).
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/11680

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