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

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; Vincent R. Zecchini; Paul S. Rennie; Aria Baniahmad; Simon Tavaré; Ian G. Mills; Yaron Galanty; Nicola Crosetto; Niklas Schultz; David Neal; Thomas Helleday

doi:10.1038/s41467-017-00393-y

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

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

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

Research output: Contribution to journal › Article › peer-review

259 Scopus citations

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.

Original language	English
Article number	374
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00393-y
State	Published - Dec 1 2017
Externally published	Yes

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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., ... Helleday, T. (2017). Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nature Communications , 8(1), Article 374. https://doi.org/10.1038/s41467-017-00393-y

@article{8b783eb1315c49febea974dedee61bdb,

title = "Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer",

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.",

author = "Mohammad Asim and Firas Tarish and Zecchini, \{Heather I.\} and Kumar Sanjiv and Eleni Gelali and Massie, \{Charles E.\} and Ajoeb Baridi and Warren, \{Anne Y.\} and Wanfeng Zhao and Christoph Ogris and McDuffus, \{Leigh Anne\} and Patrice Mascalchi and Greg Shaw and Harveer Dev and Karan Wadhwa and Paul Wijnhoven and Forment, \{Josep V.\} and Lyons, \{Scott R.\} and Lynch, \{Andy G.\} and Cormac O'Neill and Zecchini, \{Vincent R.\} and Rennie, \{Paul S.\} and Aria Baniahmad and Simon Tavar{\'e} and Mills, \{Ian G.\} and Yaron Galanty and Nicola Crosetto and Niklas Schultz and David Neal and Thomas Helleday",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-00393-y",

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Asim, M, Tarish, F, Zecchini, HI, Sanjiv, K, Gelali, E, Massie, CE, Baridi, A, Warren, AY, Zhao, W, Ogris, C, McDuffus, LA, Mascalchi, P, Shaw, G, Dev, H, Wadhwa, K, Wijnhoven, P, Forment, JV, Lyons, SR, Lynch, AG, O'Neill, C, Zecchini, VR, Rennie, PS, Baniahmad, A, Tavaré, S, Mills, IG, 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, no. 1, 374. https://doi.org/10.1038/s41467-017-00393-y

TY - JOUR

T1 - Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer

AU - Asim, Mohammad

AU - Tarish, Firas

AU - Zecchini, Heather I.

AU - Sanjiv, Kumar

AU - Gelali, Eleni

AU - Massie, Charles E.

AU - Baridi, Ajoeb

AU - Warren, Anne Y.

AU - Zhao, Wanfeng

AU - Ogris, Christoph

AU - McDuffus, Leigh Anne

AU - Mascalchi, Patrice

AU - Shaw, Greg

AU - Dev, Harveer

AU - Wadhwa, Karan

AU - Wijnhoven, Paul

AU - Forment, Josep V.

AU - Lyons, Scott R.

AU - Lynch, Andy G.

AU - O'Neill, Cormac

AU - Zecchini, Vincent R.

AU - Rennie, Paul S.

AU - Baniahmad, Aria

AU - Tavaré, Simon

AU - Mills, Ian G.

AU - Galanty, Yaron

AU - Crosetto, Nicola

AU - Schultz, Niklas

AU - Neal, David

AU - Helleday, Thomas

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85028448581

U2 - 10.1038/s41467-017-00393-y

DO - 10.1038/s41467-017-00393-y

M3 - Artículo

C2 - 28851861

AN - SCOPUS:85028448581

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 374

ER -

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

Abstract

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