Bian Xing, Sun Chuanbo, Cheng Jin, Hong Bo
College of Biological and Pharmaceutical Engineering, West Anhui University, Lu'an 237012, China.
Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.
Pharmaceutics. 2023 Aug 30;15(9):2241. doi: 10.3390/pharmaceutics15092241.
The dependence of cancer cells on the DNA damage response (DDR) pathway for the repair of endogenous- or exogenous-factor-induced DNA damage has been extensively studied in various cancer types, including endometrial cancer (EC). Targeting one or more DNA damage repair protein with small molecules has shown encouraging treatment efficacy in preclinical and clinical models. However, the genes coding for DDR factors are rarely mutated in EC, limiting the utility of DDR inhibitors in this disease. In the current review, we recapitulate the functional role of the DNA repair system in the development and progression of cancer. Importantly, we discuss strategies that target DDR proteins, including PARP, CHK1 and WEE1, as monotherapies or in combination with cytotoxic agents in the treatment of EC and highlight the compounds currently being evaluated for their efficacy in EC in clinic. Recent studies indicate that the application of DNA damage agents in cancer cells leads to the activation of innate and adaptive immune responses; targeting immune checkpoint proteins could overcome the immune suppressive environment in tumors. We further summarize recently revolutionized immunotherapies that have been completed or are now being evaluated for their efficacy in advanced EC and propose future directions for the development of DDR-based cancer therapeutics in the treatment of EC.
癌细胞对内源性或外源性因素诱导的DNA损伤修复所依赖的DNA损伤反应（DDR）途径，已在包括子宫内膜癌（EC）在内的多种癌症类型中得到广泛研究。在临床前和临床模型中，用小分子靶向一种或多种DNA损伤修复蛋白已显示出令人鼓舞的治疗效果。然而，编码DDR因子的基因在EC中很少发生突变，这限制了DDR抑制剂在该疾病中的应用。在本综述中，我们概述了DNA修复系统在癌症发生和发展中的功能作用。重要的是，我们讨论了靶向DDR蛋白（包括PARP、CHK1和WEE1）的策略，这些策略作为单一疗法或与细胞毒性药物联合用于治疗EC，并强调了目前正在临床评估其对EC疗效的化合物。最近的研究表明，在癌细胞中应用DNA损伤剂会导致先天性和适应性免疫反应的激活；靶向免疫检查点蛋白可以克服肿瘤中的免疫抑制环境。我们进一步总结了最近在晚期EC中已完成或正在评估其疗效的彻底变革性免疫疗法，并提出了基于DDR的癌症治疗在EC治疗中的未来发展方向。
