Recent Advances in Synergistic Antitumor Effects Exploited from the Inhibition of Ataxia Telangiectasia and RAD3-Related Protein Kinase (ATR).
Recent Advances in Synergistic Antitumor Effects Exploited from the Inhibition of Ataxia Telangiectasia and RAD3-Related Protein Kinase (ATR).
复制标题
DOI：
10.3390/molecules27082491
复制
发表时间：
2022-04-12
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
共济失调毛细血管扩张症和RAD 3相关蛋白激酶（ATR）是磷脂酰肌醇3-激酶相关激酶（PIKKs）家族的重要成员之一，在维持哺乳动物细胞DNA损伤反应（DDR）和修复途径的基因组完整性方面起着至关重要的作用。ATR的失调已在不同的癌症类型中发现。近年来，在临床前和临床研究中，ATR的抑制已被证明在癌症治疗中是有效的。重要的是，肿瘤特异性改变，如ATM丢失和细胞周期蛋白E1（CCNE 1）扩增对ATR抑制更敏感，并被用于合成致死（SL）策略。除了SL，近年来越来越多地报道了涉及ATRi的协同抗癌作用。本文综述了不同形式协同抗肿瘤作用的最新进展，总结了生物学机制背后的药理学益处和正在进行的临床试验，并展望了未来的挑战和机遇。希望引起社会的认识，靶向ATR应该有很大的潜力，在开发有效的抗癌药物。
As one of the key phosphatidylinositol 3-kinase-related kinases (PIKKs) family members, ataxia telangiectasia and RAD3-related protein kinase (ATR) is crucial in maintaining mammalian cell genomic integrity in DNA damage response (DDR) and repair pathways. Dysregulation of ATR has been found across different cancer types. In recent years, the inhibition of ATR has been proven to be effective in cancer therapy in preclinical and clinical studies. Importantly, tumor-specific alterations such as ATM loss and Cyclin E1 (CCNE1) amplification are more sensitive to ATR inhibition and are being exploited in synthetic lethality (SL) strategy. Besides SL, synergistic anticancer effects involving ATRi have been reported in an increasing number in recent years. This review focuses on the recent advances in different forms of synergistic antitumor effects, summarizes the pharmacological benefits and ongoing clinical trials behind the biological mechanism, and provides perspectives for future challenges and opportunities. The hope is to draw awareness to the community that targeting ATR should have great potential in developing effective anticancer medicines.
登录
查看更多内容
影响因子：
10.1
作者：
Chaudhuri, Leena;Vincelette, Nicole D.;Tibes, Raoul
通讯作者：
Tibes, Raoul
DOI：
10.1073/pnas.1921649117
发表时间：
2020-02-25
影响因子：
11.1
作者：
Bruno, Peter M.;Lu, Mengrou;Pritchard, Justin R.
通讯作者：
Pritchard, Justin R.
影响因子：
4
作者：
Chory EJ;Kirkland JG;Chang CY;D'Andrea VD;Gourisankar S;Dykhuizen EC;Crabtree GR
通讯作者：
Crabtree GR
DOI：
10.1073/pnas.93.7.2850
发表时间：
1996-04-02
影响因子：
11.1
作者：
Cimprich, KA;Shin, TB;Schreiber, SL
通讯作者：
Schreiber, SL
影响因子：
5.7
作者：
Baschnagel AM;Elnaggar JH;VanBeek HJ;Kromke AC;Skiba JH;Kaushik S;Abel L;Clark PA;Longhurst CA;Nickel KP;Leal TA;Zhao SG;Kimple RJ
通讯作者：
Kimple RJ