Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970.
Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970.
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DOI：
10.18632/oncotarget.2158
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发表时间：
2014-07-30
期刊：
影响因子：
--
通讯作者：
Pollard JR
中科院分区：
文献类型：
--
作者：
Hall AB;Newsome D;Wang Y;Boucher DM;Eustace B;Gu Y;Hare B;Johnson MA;Milton S;Murphy CE;Takemoto D;Tolman C;Wood M;Charlton P;Charrier JD;Furey B;Golec J;Reaper PM;Pollard JR
基于铂的DNA损伤化疗是大多数肺癌患者的标准治疗，但结果仍然很差。这部分归功于被称为DNA损伤反应（DDR）的高效修复网络。ATR激酶是该途径的关键调节剂，并且其抑制已显示在体外使一些癌细胞而非正常细胞对DNA损伤剂敏感。然而，ATR抑制的体内概念验证数据有限。为了解决这个问题，我们在一系列体外和体内肺癌模型中分析了VX-970（第一种临床ATR抑制剂），并将其与下游激酶Chk 1的抑制剂进行了比较。VX-970在体外对多种DNA损伤药物显着致敏大部分肺癌细胞系和原发性肿瘤组，观察到Chk 1抑制的明显差异。在体内，VX-970阻断了肿瘤中的ATR活性，并显著增强了顺铂在一组患者来源的原发性肺异种移植物中的疗效。该组合在三种顺铂不敏感模型中导致完全的肿瘤生长抑制，在顺铂敏感模型中导致持久的肿瘤消退。这些数据为VX-970在肺癌患者中的临床评价提供了强有力的依据。
Platinum-based DNA-damaging chemotherapy is standard-of-care for most patients with lung cancer but outcomes remain poor. This has been attributed, in part, to the highly effective repair network known as the DNA-damage response (DDR). ATR kinase is a critical regulator of this pathway, and its inhibition has been shown to sensitize some cancer, but not normal, cells in vitro to DNA damaging agents. However, there are limited in vivo proof-of-concept data for ATR inhibition. To address this we profiled VX-970, the first clinical ATR inhibitor, in a series of in vitro and in vivo lung cancer models and compared it with an inhibitor of the downstream kinase Chk1. VX-970 markedly sensitized a large proportion of a lung cancer cell line and primary tumor panel in vitro to multiple DNA damaging drugs with clear differences to Chk1 inhibition observed. In vivo VX-970 blocked ATR activity in tumors and dramatically enhanced the efficacy of cisplatin across a panel of patient derived primary lung xenografts. The combination led to complete tumor growth inhibition in three cisplatin-insensitive models and durable tumor regression in a cisplatin-sensitive model. These data provide a strong rationale for the clinical evaluation of VX-970 in lung cancer patients.
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影响因子：
11.2
作者：
Gilad O;Nabet BY;Ragland RL;Schoppy DW;Smith KD;Durham AC;Brown EJ
通讯作者：
Brown EJ
影响因子：
11.2
作者：
Hammond, EM;Dorie, MJ;Giaccia, AJ
通讯作者：
Giaccia, AJ
影响因子：
158.5
作者：
Hegi, ME;Diserens, A;Stupp, R
通讯作者：
Stupp, R
影响因子：
4.7
作者：
Carser, Judith E.;Quinn, Jennifer E.;Harkin, D. Paul
通讯作者：
Harkin, D. Paul
人类癌基因组中体细胞突变的模式。
影响因子：
64.8
作者：
Greenman, Christopher;Stephens, Philip;Smith, Raffaella;Dalgliesh, Gillian L.;Hunter, Christopher;Bignell, Graham;Davies, Helen;Teague, Jon;Butler, Adam;Edkins, Sarah;O'Meara, Sarah;Vastrik, Imre;Schmidt, Esther E.;Avis, Tim;Barthorpe, Syd;Bhamra, Gurpreet;Buck, Gemma;Choudhury, Bhudipa;Clements, Jody;Cole, Jennifer;Dicks, Ed;Forbes, Simon;Gray, Kris;Halliday, Kelly;Harrison, Rachel;Hills, Katy;Hinton, Jon;Jenkinson, Andy;Jones, David;Menzies, Andy;Mironenko, Tatiana;Perry, Janet;Raine, Keiran;Richardson, Dave;Shepherd, Rebecca;Small, Alexandra;Tofts, Calli;Varian, Jennifer;Webb, Tony;West, Sofie;Widaa, Sara;Yates, Andy;Cahill, Daniel P.;Louis, David N.;Goldstraw, Peter;Nicholson, Andrew G.;Brasseur, Francis;Looijenga, Leendert;Weber, Barbara L.;Chiew, Yoke-Eng;deFazio, Anna;Greaves, Mel F.;Green, Anthony R.;Campbell, Peter;Birney, Ewan;Easton, Douglas F.;Chenevix-Trench, Georgia;Tan, Min-Han;Khoo, Sok Kean;Teh, Bin Tean;Yuen, Siu Tsan;Leung, Suet Yi;Wooster, Richard;Futreal, P. Andrew;Stratton, Michael R.
通讯作者：
Stratton, Michael R.