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ATM in DNA repair in cancer.
Pharmacology & Therapeutics ( IF 12.0 ) Pub Date : 2019-07-09 , DOI: 10.1016/j.pharmthera.2019.07.002
Mei Hua Jin 1 , Do-Youn Oh 2
Affiliation  

Alterations in DNA damage response (DDR) pathways are hallmarks of cancer. Incorrect repair of DNA lesions often leads to genomic instability. Ataxia telangiectasia mutated (ATM), a core component of the DNA repair system, is activated to enhance the homologous recombination (HR) repair pathway upon DNA double-strand breaks. Although ATM signaling has been widely studied in different types of cancer, its research is still lacking compared with other DDR-involved molecules such as PARP and ATR. There is still a vast research opportunity for the development of ATM inhibitors as anticancer agents. Here, we focus on the recent findings of ATM signaling in DNA repair of cancer. Previous studies have identified several partners of ATM, some of which promote ATM signaling, while others have the opposite effect. ATM inhibitors, including KU-55933, KU-60019, KU-59403, CP-466722, AZ31, AZ32, AZD0156, and AZD1390, have been evaluated for their antitumor effects. It has been revealed that ATM inhibition increases a cancer cell's sensitivity to radiotherapy. Moreover, the combination with PARP or ATR inhibitors has synergistic lethality in some cancers. Of note, among these ATM inhibitors, AZD0156 and AZD1390 achieve potent and highly selective ATM kinase inhibition and have an excellent ability to penetrate the blood-brain barrier. Currently, AZD0156 and AZD1390 are under investigation in phase I clinical trials. Taken together, targeting ATM may be a promising strategy for cancer treatment. Hence, further development of ATM inhibitors is urgently needed in cancer research.

中文翻译:

ATM在癌症的DNA修复中。

DNA损伤反应(DDR)途径的改变是癌症的标志。DNA损伤的修复不正确通常会导致基因组不稳定。DNA修复系统的核心组成部分共济失调毛细血管扩张症(ATM)被激活以增强DNA双链断裂后的同源重组(HR)修复途径。尽管已经在不同类型的癌症中对ATM信号进行了广泛的研究,但与其他DDR涉及的分子(如PARP和ATR)相比,仍缺乏对ATM信号的研究。ATM抑制剂作为抗癌药的开发仍然有巨大的研究机会。在这里,我们关注于癌症的DNA修复中ATM信号转导的最新发现。先前的研究已经确定了ATM的几个合作伙伴,其中一些促进ATM信号传输,而另一些则相反。ATM抑制剂,包括KU-55933,评估了KU-60019,KU-59403,CP-466722,AZ31,AZ32,AZD0156和AZ​​D1390的抗肿瘤作用。已经发现,ATM抑制增加了癌细胞对放射疗法的敏感性。此外,与PARP或ATR抑制剂的组合在某些癌症中具有协同杀伤力。值得注意的是,在这些ATM抑制剂中,AZD0156和AZ​​D1390实现了有效且高度选择性的ATM激酶抑制作用,并具有出色的穿透血脑屏障的能力。目前,I期临床试验中正在研究AZD0156和AZ​​D1390。两者合计,针对ATM可能是一种有前途的癌症治疗策略。因此,在癌症研究中迫切需要进一步开发ATM抑制剂。已经发现,ATM抑制增加了癌细胞对放射疗法的敏感性。此外,与PARP或ATR抑制剂的组合在某些癌症中具有协同杀伤力。值得注意的是,在这些ATM抑制剂中,AZD0156和AZ​​D1390实现了有效且高度选择性的ATM激酶抑制作用,并具有出色的穿透血脑屏障的能力。目前,I期临床试验中正在研究AZD0156和AZ​​D1390。两者合计,针对ATM可能是一种有前途的癌症治疗策略。因此,在癌症研究中迫切需要进一步开发ATM抑制剂。已经发现,ATM抑制增加了癌细胞对放射疗法的敏感性。此外,与PARP或ATR抑制剂的组合在某些癌症中具有协同杀伤力。值得注意的是,在这些ATM抑制剂中,AZD0156和AZ​​D1390实现了有效且高度选择性的ATM激酶抑制作用,并具有出色的穿透血脑屏障的能力。目前,I期临床试验中正在研究AZD0156和AZ​​D1390。两者合计,针对ATM可能是一种有前途的癌症治疗策略。因此,在癌症研究中迫切需要进一步开发ATM抑制剂。AZD0156和AZ​​D1390实现了有效且高度选择性的ATM激酶抑制作用,并具有出色的穿透血脑屏障的能力。目前,I期临床试验中正在研究AZD0156和AZ​​D1390。两者合计,针对ATM可能是一种有前途的癌症治疗策略。因此,在癌症研究中迫切需要进一步开发ATM抑制剂。AZD0156和AZ​​D1390实现了有效且高度选择性的ATM激酶抑制作用,并具有出色的穿透血脑屏障的能力。目前,I期临床试验中正在研究AZD0156和AZ​​D1390。两者合计,针对ATM可能是一种有前途的癌症治疗策略。因此,在癌症研究中迫切需要进一步开发ATM抑制剂。
更新日期:2019-11-18
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