表皮生长因子受体通路底物8号（EPS8）被报道为在介导肿瘤进展中至关重要。然而，EPS8过度表达的分子和生物学后果仍然不清楚。在这里，我们评估了EPS8是否增加了非小细胞肺癌（NSCLC）细胞中的DNA损伤修复以及EPS8介导的影响化疗敏感性的DNA损伤修复机制。功能实验的连续研究揭示了EPS8敲除抑制了细胞生长，诱导了细胞周期停滞，并增加了对NSCLC的顺铂治疗效果。发现EPS8通过上调磷酸化ATM和下调肿瘤抑制剂p53及G1细胞激酶抑制剂p21来诱导DNA损伤修复。此外，与顺铂配合使用，降低EPS8蛋白水平进一步增加了p53蛋白水平并抑制了ATM信号传导。还进行了移植肿瘤研究，证明EPS8敲除抑制了肿瘤生长并增强了肿瘤对顺铂的敏感性。总之，我们描述了EPS8可能参与癌症进展和化疗抗性的新型分子机制，即通过DNA损伤修复，表明EPS8表达可能影响化疗反应。因此，靶向EPS8可能是治疗NSCLC患者的潜在治疗方法。 ©2023。作者，独家许可Springer Nature America，Inc.

Epidermal growth factor receptor pathway substrate number 8 (EPS8) has been reported to be critical in mediating tumor progression. However, the molecular and biological consequences of EPS8 overexpression remain unclear. Here we evaluated whether EPS8 increased DNA damage repair in non-small-cell lung carcinoma (NSCLC) cells and the mechanism of EPS8-mediated DNA damage repair which influenced chemosensitivity. Serial studies of functional experiments revealed that EPS8 knockdown inhibited cell growth, induced cell-cycle arrest and increased cisplatin therapeutic effects on NSCLC. EPS8 was found to induce DNA damage repair via upregulation of phosphorylated-ATM and downregulation of the tumor suppressor p53 and G1 cell kinase inhibitor p21. Moreover, in conjunction with cisplatin, decreasing EPS8 protein levels further increased p53 protein level and inhibited ATM signaling. Transplanted tumor studies were also performed to demonstrate that EPS8 knockdown inhibited tumor growth and sensitized tumors to cisplatin treatment. In conclusion, we have described a novel molecular mechanism through which EPS8 is likely to be involved in cancer progression and chemoresistance via DNA damage repair, indicating that EPS8 expression may influence the response to chemotherapy. Therefore, targeting EPS8 may be a potential therapeutic approach for patients with NSCLC.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.