DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy.
DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy.
复制标题
DNA 损伤修复：癌症靶向治疗的历史观点、机制途径和临床转化
DOI：
10.1038/s41392-021-00648-7
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发表时间：
2021-07-09
影响因子：
39.3
通讯作者：
Zhou PK
中科院分区：
文献类型：
--
作者：
Huang R;Zhou PK
基因组不稳定性是各种癌症的标志，随着DNA损伤的积累而增加。放疗和化疗在癌症治疗中的应用通常基于癌症的这种性质。然而，放疗和化疗也伴随着包括正常组织损伤在内的不良反应。靶向癌症治疗具有通过针对缺乏特异性DNA损伤反应功能的癌症患者的定制治疗来抑制癌细胞的DNA损伤反应的潜力。显然，理解DNA损伤修复在癌症中的更广泛作用已成为癌症靶向治疗的基本和有吸引力的策略，特别是，在此领域的基础上提出新的假说或理论对于未来有希望的药物新兴靶点将是重要的。本文首先阐述了DNA损伤修复在肿瘤发生发展中的作用和肿瘤治疗的时间轴，然后总结了肿瘤靶向治疗中DNA损伤修复的作用机制，重点介绍了靶向DNA损伤修复的特异性蛋白质，这些蛋白质在环境DNA损伤因子的外源性损伤作用下启动异常功能，DNA损伤基线漂移导致有害的内在靶向癌症治疗。此外，还对DNA损伤修复的临床治疗药物，包括治疗效果，以及相关临床试验的策略和方案进行了深入的讨论。基于这一背景，我们提出了两个假说，即“环境齿轮选择”来描述DNA损伤修复途径的演变，和“DNA损伤基线漂移”，这可能在癌症治疗期间介导修复中发挥放大作用。这两个新的假说将为肿瘤靶向治疗提供新的思路，提供更好或更全面的整体观，并促进新的研究方向和患者新的克服策略的发展。
Genomic instability is the hallmark of various cancers with the increasing accumulation of DNA damage. The application of radiotherapy and chemotherapy in cancer treatment is typically based on this property of cancers. However, the adverse effects including normal tissues injury are also accompanied by the radiotherapy and chemotherapy. Targeted cancer therapy has the potential to suppress cancer cells’ DNA damage response through tailoring therapy to cancer patients lacking specific DNA damage response functions. Obviously, understanding the broader role of DNA damage repair in cancers has became a basic and attractive strategy for targeted cancer therapy, in particular, raising novel hypothesis or theory in this field on the basis of previous scientists’ findings would be important for future promising druggable emerging targets. In this review, we first illustrate the timeline steps for the understanding the roles of DNA damage repair in the promotion of cancer and cancer therapy developed, then we summarize the mechanisms regarding DNA damage repair associated with targeted cancer therapy, highlighting the specific proteins behind targeting DNA damage repair that initiate functioning abnormally duo to extrinsic harm by environmental DNA damage factors, also, the DNA damage baseline drift leads to the harmful intrinsic targeted cancer therapy. In addition, clinical therapeutic drugs for DNA damage and repair including therapeutic effects, as well as the strategy and scheme of relative clinical trials were intensive discussed. Based on this background, we suggest two hypotheses, namely “environmental gear selection” to describe DNA damage repair pathway evolution, and “DNA damage baseline drift”, which may play a magnified role in mediating repair during cancer treatment. This two new hypothesis would shed new light on targeted cancer therapy, provide a much better or more comprehensive holistic view and also promote the development of new research direction and new overcoming strategies for patients.
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影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
7.4
作者：
Abbotts R;Wilson DM 3rd
通讯作者：
Wilson DM 3rd
DNA复制叉的终止：“分手很难做到”。
DOI：
10.1080/19491034.2015.1035843
发表时间：
2015
期刊：
Nucleus (Austin, Tex.)
影响因子：
--
作者：
Bailey R;Priego Moreno S;Gambus A
通讯作者：
Gambus A
影响因子：
14.9
作者：
Ahrabi S;Sarkar S;Pfister SX;Pirovano G;Higgins GS;Porter AC;Humphrey TC
通讯作者：
Humphrey TC
影响因子：
4.7
作者：
Baptisteila, Antuani Rafael;Landemberger, Michele Christine;Martins, Ilma Regina
通讯作者：
Martins, Ilma Regina