Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.
Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.
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DOI：
10.1038/s41467-021-23463-8
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发表时间：
2021-06-17
影响因子：
16.6
通讯作者：
Lord CJ
中科院分区：
文献类型：
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作者：
Zatreanu D;Robinson HMR;Alkhatib O;Boursier M;Finch H;Geo L;Grande D;Grinkevich V;Heald RA;Langdon S;Majithiya J;McWhirter C;Martin NMB;Moore S;Neves J;Rajendra E;Ranzani M;Schaedler T;Stockley M;Wiggins K;Brough R;Sridhar S;Gulati A;Shao N;Badder LM;Novo D;Knight EG;Marlow R;Haider S;Callen E;Hewitt G;Schimmel J;Prevo R;Alli C;Ferdinand A;Bell C;Blencowe P;Bot C;Calder M;Charles M;Curry J;Ekwuru T;Ewings K;Krajewski W;MacDonald E;McCarron H;Pang L;Pedder C;Rigoreau L;Swarbrick M;Wheatley E;Willis S;Wong AC;Nussenzweig A;Tijsterman M;Tutt A;Boulton SJ;Higgins GS;Pettitt SJ;Smith GCM;Lord CJ
为了确定靶向癌症DNA修复脆弱性的方法，我们发现了纳米摩尔强效、选择性、低分子量（MW）的DNA聚合酶Polθ功能变抗抑制剂，包括ART558。ART558抑制主要的polθ介导的DNA修复过程，theta介导的末端连接，而不靶向非同源末端连接。此外，ART558在BRCA1-或brca2突变肿瘤细胞中引发DNA损伤和合成致死，并增强PARP抑制剂的作用。遗传扰动筛选显示，53BP1/ shield复合物的缺陷导致PARP抑制剂耐药，导致体外和体内对小分子Polθ聚合酶抑制剂敏感。在机制上，ART558增加了53bp1缺陷细胞中单链DNA的生物标志物和合成致死性，而抑制促进末端切除的DNA核酸酶逆转了这些作用，暗示这些作用与合成致死性作用机制有关。综上所述，这些观察结果描述了一类引发brca基因合成致死率和PARP抑制剂协同作用的药物，以及针对parpi耐药的生物标志物定义机制。Polθ最近被确定为癌症的治疗靶点，但目前还没有特定的抑制剂。本研究中，作者发现了Polθ聚合酶活性的小分子抑制剂，可引发BRCA1/2合成致死，增强PARP抑制剂的效果，并针对53BP1/ shield通路缺陷引起的PARP抑制剂耐药。
To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining, without targeting Non-Homologous End Joining. In addition, ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a PARP inhibitor. Genetic perturbation screening revealed that defects in the 53BP1/Shieldin complex, which cause PARP inhibitor resistance, result in in vitro and in vivo sensitivity to small molecule Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells whilst the inhibition of DNA nucleases that promote end-resection reversed these effects, implicating these in the synthetic lethal mechanism-of-action. Taken together, these observations describe a drug class that elicits BRCA-gene synthetic lethality and PARP inhibitor synergy, as well as targeting a biomarker-defined mechanism of PARPi-resistance. Polθ has been recently identified as a therapeutic target in cancer but specific inhibitors are currently unavailable. Here, the authors identify small molecule inhibitors of Polθ’s polymerase activity which elicit BRCA1/2 synthetic lethality, enhance the effect of PARP inhibitors and target PARP inhibitor resistance caused by 53BP1/Shieldin pathway defects.
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DOI：
10.15252/embj.2018100158
发表时间：
2018-09-14
期刊：
The EMBO journal
影响因子：
--
作者：
Findlay S;Heath J;Luo VM;Malina A;Morin T;Coulombe Y;Djerir B;Li Z;Samiei A;Simo-Cheyou E;Karam M;Bagci H;Rahat D;Grapton D;Lavoie EG;Dove C;Khaled H;Kuasne H;Mann KK;Klein KO;Greenwood CM;Tabach Y;Park M;Côté JF;Masson JY;Maréchal A;Orthwein A
通讯作者：
Orthwein A
影响因子：
16.8
作者：
Kent, Tatiana;Chandramouly, Gurushankar;McDevitt, Shane Michael;Ozdemir, Ahmet Y.;Pomerantz, Richard T.
通讯作者：
Pomerantz, Richard T.
影响因子：
3.7
作者：
Di Z;Klop MJ;Rogkoti VM;Le Dévédec SE;van de Water B;Verbeek FJ;Price LS;Meerman JH
通讯作者：
Meerman JH
影响因子：
21.3
作者：
Dev H;Chiang TW;Lescale C;de Krijger I;Martin AG;Pilger D;Coates J;Sczaniecka-Clift M;Wei W;Ostermaier M;Herzog M;Lam J;Shea A;Demir M;Wu Q;Yang F;Fu B;Lai Z;Balmus G;Belotserkovskaya R;Serra V;O'Connor MJ;Bruna A;Beli P;Pellegrini L;Caldas C;Deriano L;Jacobs JJL;Galanty Y;Jackson SP
通讯作者：
Jackson SP
影响因子：
16.6
作者：
Koole, Wouter;van Schendel, Robin;Tijsterman, Marcel
通讯作者：
Tijsterman, Marcel