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

被引：212

作者：

Asim, Mohammad ^{[1
,2
]}

Tarish, Firas ^{[3
,4
]}

Zecchini, Heather I. ^{[1
]}

Sanjiv, Kumar ^{[3
]}

Gelali, Eleni ^{[3
]}

Massie, Charles E. ^{[1
]}

Baridi, Ajoeb ^{[1
]}

Warren, Anne Y. ^{[5
]}

Zhao, Wanfeng ^{[5
]}

Ogris, Christoph ^{[3
]}

McDuffus, Leigh-Anne ^{[1
]}

Mascalchi, Patrice ^{[1
]}

Shaw, Greg ^{[1
]}

Dev, Harveer ^{[1
]}

Wadhwa, Karan ^{[1
]}

Wijnhoven, Paul ^{[6
]}

Forment, Josep V. ^{[6
]}

Lyons, Scott R. ^{[1
]}

Lynch, Andy G. ^{[1
]}

O'Neill, Cormac ^{[1
]}

Zecchini, Vincent R. ^{[1
]}

Rennie, Paul S. ^{[7
]}

Baniahmad, Aria ^{[8
]}

Tavare, Simon ^{[1
]}

Mills, Ian G. ^{[9
,10
]}

Galanty, Yaron ^{[6
]}

Crosetto, Nicola ^{[3
]}

Schultz, Niklas ^{[3
]}

Neal, David ^{[1
,11
]}

Helleday, Thomas ^{[3
]}

机构：

[1] Univ Cambridge, Canc Res UK Inst, Li Ka Shing Ctr, Cambridge CB2 0RE, England

[2] Univ Surrey, Dept Clin & Expt Med, Guildford GU2 7WG, Surrey, England

[3] Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, S-17121 Stockholm, Sweden

[4] Cent Hosp Vasteras, Dept Urol, S-72189 Vasteras, Sweden

[5] Addenbrookes Cambridge Univ Hosp, Dept Pathol, Cambridge CB2 0QQ, England

[6] Univ Cambridge, Wellcome Trust & Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England

[7] Univ British Columbia, Vancouver Prostate Ctr, Dept Urol Sci, Vancouver, BC V6H 3Z6, Canada

[8] Jena Univ Hosp, Inst Human Genet, D-07743 Jena, Germany

[9] Univ Oslo, Ctr Mol Med Norway, Nord European Mol Biol Lab Partnership, N-0318 Oslo, Norway

[10] Queens Univ, Prostate Canc UK Movember Ctr Excellence, Belfast BT9 7AE, Antrim, North Ireland

[11] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Surg, Headley Way, Oxford OX3 9DU, England

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

瑞典研究理事会;

关键词：

DNA-REPAIR; THERAPY; QUANTIFICATION; INHIBITION; POLYMERASE;

D O I：

10.1038/s41467-017-00393-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：10

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