Targeting Non-homologous and Alternative End Joining Repair to Enhance Cancer Radiosensitivity
Targeting Non-homologous and Alternative End Joining Repair to Enhance Cancer Radiosensitivity
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DOI：
10.1016/j.semradonc.2021.09.007
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发表时间：
2021-11-30
影响因子：
3.5
通讯作者：
Gupta, Gaorav P.
中科院分区：
文献类型：
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作者：
Feng, Wanjuan;Smith, Chelsea M.;Gupta, Gaorav P.
许多癌症治疗，包括放疗，诱导dsb作为诱导癌细胞死亡的主要驱动机制。因此，调节DSB修复具有巨大的放射增敏潜力，尽管这种干预措施必须仔细设计为肿瘤选择性，以确保正常组织毒性不会增加。在这里，我们回顾了容易出错的DSB修复机制，通过一个高效的过程称为末端连接。末端连接修复有两种主要途径：非同源末端连接（non-homologous end joining， NHEJ）和替代末端连接（alternative end joining, a-EJ），这两种途径在癌症中都可以选择性上调，因此代表了有吸引力的放射增敏治疗靶点。这些EJ通路都有治疗上可靶向的先锋因子- NHEJ的DNA依赖性蛋白激酶催化亚基（DNA- pkcs）和a-EJ的DNA聚合酶Theta （Pol Theta）。我们总结了NHEJ和a-EJ靶向治疗以提高放疗效果的现状，重点介绍了必须克服的挑战和需要进一步探索的机遇。通过对癌症中DSB修复程序改变机制的临床前研究，通过NHEJ和/或a- ej靶向选择性放射致敏仍然是正在进行和未来临床研究的一个极具吸引力的途径。(C) 2021年由Elsevier Inc.出版。
Many cancer therapies, including radiotherapy, induce DSBs as the major driving mechanism for inducing cancer cell death. Thus, modulating DSB repair has immense potential for radiosensitization, although such interventions must be carefully designed to be tumor selective to ensure that normal tissue toxicities are not also increased. Here, we review mechanisms of error-prone DSB repair through a highly efficient process called end joining. There are two major pathways of end-joining repair: non-homologous end joining (NHEJ) and alternative end joining (a-EJ), both of which can be selectively upregulated in cancer and thus represent attractive therapeutic targets for radiosensitization. These EJ pathways each have therapeutically targetable pioneer factors - DNA-dependent protein kinase catalytic subunit (DNA-PKcs) for NHEJ and DNA Polymerase Theta (Pol theta) for a-EJ. We summarize the current status of therapeutic targeting of NHEJ and a-EJ to enhance the effects of radiotherapy - focusing on challenges that must be overcome and opportunities that require further exploration. By leveraging preclinical insights into mechanisms of altered DSB repair programs in cancer, selective radiosensitization through NHEJ and/or a-EJ targeting remains a highly attractive avenue for ongoing and future clinical investigation. (C) 2021 Published by Elsevier Inc.