Inducing DNA damage is known to be one of the mechanisms of cytotoxic chemotherapy agents for cancer such as cisplatin. The endogenous DNA damage response confers chemoresistance to these agents by repairing DNA damage. The initiation and transduction of the DNA damage response (DDR) signaling pathway, which is dependent on the activation of ATM (ataxia-telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3-related), is essential for DNA damage repair, the maintenance of genomic stability and cell survival. Therefore, ATM or ATR inhibition is considered as a promising strategy for sensitizing cancer cells to chemotherapy. This study is aimed to explore the effect of ATR inhibitor on sensitizing ESCC (esophageal squamous cell carcinoma) cells to cisplatin, and whether ATM deficiency could impact the sensitization. We found that 21.5% of ESCC cases had ATM deficiency and that patients with ATR activation after neoadjuvant chemotherapy had worse chemotherapy response and poorer overall survival than that without ATR activation (32 mons vs. >140mons). Then, it was shown that VE-822 inhibited ATR-CHK1 pathway activation, leading to the accumulation of cisplatin-modified DNA. And it inhibited cell proliferation, induced cell cycle arrest in G1 phase and enhanced cell apoptosis. Moreover, VE-822 significantly sensitized ESCC cells to cisplatin, and these two drugs had synergistic effects, especially in ATM-deficient cells, in vitro and in vivo. Our results suggest that ATR inhibition combining with cisplatin is a new strategy for managing patients with ESCC, especially those with ATM-deficiency. However, this is an idea that requires further validation.

众所周知，诱导DNA损伤是细胞毒性化疗药物（例如顺铂）的机制之一。内源性DNA损伤应答通过修复DNA损伤而赋予这些药物化学抗性。DNA损伤应答（DDR）信号通路的启动和转导取决于ATM（共济失调毛细血管扩张突变）和ATR（共济失调毛细血管扩张和Rad3相关）的激活，对于DNA损伤修复，维持基因组稳定性和细胞存活率。因此，ATM或ATR抑制被认为是使癌细胞对化学疗法敏感的一种有前途的策略。这项研究旨在探讨ATR抑制剂对食管鳞状细胞癌（ESCC）细胞对顺铂致敏性的影响，以及ATM缺乏是否会影响敏化性。我们发现21。有5％的ESCC病例有ATM缺乏症，新辅助化疗后ATR激活的患者比没有ATR激活的患者有更差的化疗反应和更差的总生存率（32个月vs.> 140个月）。然后，表明VE-822抑制了ATR-CHK1途径的活化，导致顺铂修饰的DNA的积累。并且它抑制细胞增殖，诱导细胞周期停滞在G1期并增强细胞凋亡。此外，VE-822对ESCC细胞具有明显的顺铂敏感性，并且这两种药物在体外和体内均具有协同作用，尤其是在ATM缺乏的细胞中。我们的结果表明，将ATR抑制与顺铂联合使用是治疗ESCC，尤其是ATM缺乏症患者的新策略。但是，这是一个需要进一步验证的想法。