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

被引：199

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

共 30 条

[11] Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
Farmer, H
McCabe, N
Lord, CJ
Tutt, ANJ
Johnson, DA
Richardson, TB
Santarosa, M
Dillon, KJ
Hickson, I
Knights, C
Martin, NMB
Jackson, SP
Smith, GCM
Ashworth, A
[J]. NATURE, 2005, 434 (7035) : 917 - 921
[12] A Hormone-DNA Repair Circuit Governs the Response to Genotoxic Insult
Goodwin, Jonathan F.
Schiewer, Matthew J.
Dean, Jeffry L.
Schrecengost, Randy S.
de Leeuw, Renee
Han, Sumin
Ma, Teng
Den, Robert B.
Dicker, Adam P.
Feng, Felix Y.
Knudsen, Karen E.
[J]. CANCER DISCOVERY, 2013, 3 (11) : 1254 - 1271
[13] Poly(ADP-Ribose) Polymerase Is Hyperactivated in Homologous Recombination-Defective Cells
Gottipati, Ponnari
Vischioni, Barbara
Schultz, Niklas
Solomons, Joyce
Bryant, Helen E.
Djureinovic, Tatjana
Issaeva, Natalia
Sleeth, Kate
Sharma, Ricky A.
Helleday, Thomas
[J]. CANCER RESEARCH, 2010, 70 (13) : 5389 - 5398
[14] The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings
Helleday, Thomas
[J]. MOLECULAR ONCOLOGY, 2011, 5 (04): : 387 - 393
[15] Jemal A, 2009, CA-CANCER J CLIN, V59, P225, DOI [10.3322/caac.20006, 10.3322/caac.21254, 10.3322/caac.21332, 10.3322/caac.21551, 10.3322/caac.20073, 10.3322/caac.21387, 10.3322/caac.21654, 10.3322/caac.21601]
[16] Final Report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer
Mason, Malcolm D.
Parulekar, Wendy R.
Sydes, Matthew R.
Brundage, Michael
Kirkbride, Peter
Gospodarowicz, Mary
Cowan, Richard
Kostashuk, Edmund C.
Anderson, John
Swanson, Gregory
Parmar, Mahesh K. B.
Hayter, Charles
Jovic, Gordana
Hiltz, Andrea
Hetherington, John
Sathya, Jinka
Barber, James B. P.
McKenzie, Michael
El-Sharkawi, Salah
Souhami, Luis
Hardman, P. D. John
Chen, Bingshu E.
Warde, Padraig
[J]. JOURNAL OF CLINICAL ONCOLOGY, 2015, 33 (19) : 2143 - U170
[17] The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis
Massie, Charles E.
Lynch, Andy
Ramos-Montoya, Antonio
Boren, Joan
Stark, Rory
Fazli, Ladan
Warren, Anne
Scott, Helen
Madhu, Basetti
Sharma, Naomi
Bon, Helene
Zecchini, Vinny
Smith, Donna-Michelle
DeNicola, Gina M.
Mathews, Nik
Osborne, Michelle
Hadfield, James
MacArthur, Stewart
Adryan, Boris
Lyons, Scott K.
Brindle, Kevin M.
Griffiths, John
Gleave, Martin E.
Rennie, Paul S.
Neal, David E.
Mills, Ian G.
[J]. EMBO JOURNAL, 2011, 30 (13) : 2719 - 2733
[18] DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer
Mateo, J.
Carreira, S.
Sandhu, S.
Miranda, S.
Mossop, H.
Perez-Lopez, R.
Rodrigues, D. Nava
Robinson, D.
Omlin, A.
Tunariu, N.
Boysen, G.
Porta, N.
Flohr, P.
Gillman, A.
Figueiredo, I.
Paulding, C.
Seed, G.
Jain, S.
Ralph, C.
Protheroe, A.
Hussain, S.
Jones, R.
Elliott, T.
McGovern, U.
Bianchini, D.
Goodall, J.
Zafeiriou, Z.
Williamson, C. T.
Ferraldeschi, R.
Riisnaes, R.
Ebbs, B.
Fowler, G.
Roda, D.
Yuan, W.
Wu, Y. -M.
Cao, X.
Brough, R.
Pemberton, H.
A'Hern, R.
Swain, A.
Kunju, L. P.
Eeles, R.
Attard, G.
Lord, C. J.
Ashworth, A.
Rubin, M. A.
Knudsen, K. E.
Feng, F. Y.
Chinnaiyan, A. M.
Hall, E.
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2015, 373 (18) : 1697 - 1708
[19] Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors
Murai, Junko
Huang, Shar-yin N.
Das, Benu Brata
Renaud, Amelie
Zhang, Yiping
Doroshow, James H.
Ji, Jiuping
Takeda, Shunichi
Pommier, Yves
[J]. CANCER RESEARCH, 2012, 72 (21) : 5588 - 5599
[20] Pettaway CA, 1996, CLIN CANCER RES, V2, P1627

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