Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality

被引：259

作者：

Gogola, Ewa ^{[1
,14
]}

Duarte, Alexandra A. ^{[1
,14
]}

de Ruiter, Julian R. ^{[1
,2
,14
]}

Wiegant, Wouter W. ^{[6
]}

Schmid, Jonas A. ^{[7
]}

de Bruijn, Roebi ^{[1
,2
,14
]}

James, Dominic I. ^{[8
]}

Llobet, Sergi Guerrero ^{[9
]}

Vis, Daniel J. ^{[2
,14
]}

Annunziato, Stefano ^{[1
,14
]}

van den Broek, Bram ^{[3
]}

Barazas, Marco ^{[1
,14
]}

Kersbergen, Ariena ^{[5
]}

van de Ven, Marieke ^{[4
]}

Tarsounas, Madalena ^{[10
]}

Ogilvie, Donald J. ^{[8
]}

van Vugt, Marcel ^{[9
]}

Wessels, Lodewyk F. A. ^{[2
,14
]}

Bartkova, Jirina ^{[11
,12
]}

Gromova, Irina ^{[11
]}

Andujar-Sanchez, Miguel ^{[13
]}

Bartek, Jiri ^{[11
,12
]}

Lopes, Massimo ^{[7
]}

van Attikum, Haico ^{[6
]}

Borst, Piet ^{[5
]}

Jonkers, Jos ^{[1
,14
]}

Rottenberg, Sven ^{[1
,15
]}

机构：

[1] Netherlands Canc Inst, Div Mol Pathol, NL-1066 CX Amsterdam, Netherlands

[2] Netherlands Canc Inst, Div Mol Carcinogenesis, NL-1066 CX Amsterdam, Netherlands

[3] Netherlands Canc Inst, Div Cell Biol & BioImaging Facil, NL-1066 CX Amsterdam, Netherlands

[4] Netherlands Canc Inst, Preclin Intervent Unit, MCCA, NL-1066 CX Amsterdam, Netherlands

[5] Netherlands Canc Inst, Div Mol Oncol, NL-1066 CX Amsterdam, Netherlands

[6] Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 ZC Leiden, Netherlands

[7] Univ Zurich, Inst Mol Canc Res, CH-8057 Zurich, Switzerland

[8] Univ Manchester, Canc Res UK Manchester Inst, Drug Discovery Unit, Manchester M20 4BX, Lancs, England

[9] Univ Groningen, Univ Med Ctr Groningen, Dept Med Oncol, NL-9723 GZ Groningen, Netherlands

[10] Univ Oxford, CRUK MRC Oxford Inst Radiat Oncol, Oxford OX3 7DQ, England

[11] Danish Canc Soc Res Ctr, DK-2100 Copenhagen, Denmark

[12] Karolinska Inst, Dept Med Biochem & Biophys, Div Genome Biol, Sci Life Lab, S-17177 Stockholm, Sweden

[13] Complejo Hosp Univ Insular Materno Infantil, Dept Pathol, Las Palmas Gran Canaria, Gran Canaria, Spain

[14] Canc Genom Netherlands, NL-1066 CX Amsterdam, Netherlands

[15] Univ Bern, Vetsuisse Fac, Inst Anim Pathol, CH-3012 Bern, Switzerland

来源：

CANCER CELL | 2018年 / 33卷 / 06期

基金：

欧洲研究理事会; 瑞士国家科学基金会; 新加坡国家研究基金会; 瑞典研究理事会;

关键词：

REPLICATION FORK REVERSAL; CONDITIONAL MOUSE MODEL; DNA-DAMAGE-RESPONSE; POLY(ADP-RIBOSE) POLYMERASE; HOMOLOGOUS RECOMBINATION; MAMMARY-TUMORS; REPAIR; RESISTANCE; BREAST; COMBINATION;

D O I：

10.1016/j.ccell.2018.05.008

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism. We also found the presence of PARG-negative clones in a subset of human serous ovarian and triple-negative breast cancers. PARG depletion restores PAR formation and partially rescues PARP1 signaling. Importantly, PARG inactivation exposes vulnerabilities that can be exploited therapeutically.

引用

页码：1078 / +

页数：28

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