A significant proportion of non-small cell lung cancer (NSCLC) patients experience accumulating chemotherapy-related adverse events, motivating the design of chemosensitizating strategies. The main cytotoxic damage induced by chemotherapeutic agents is DNA double-strand breaks (DSB). It is thus conceivable that DNA-dependent protein kinase (DNA-PK) inhibitors which attenuate DNA repair would enhance the anti-tumor effect of chemotherapy. The present study aims to systematically evaluate the efficacy and safety of a novel DNA-PK inhibitor M3814 in synergy with chemotherapies on NSCLC. We identified increased expression of DNA-PK in human NSCLC tissues which was associated with poor prognosis. M3814 potentiated the anti-tumor effect of paclitaxel and etoposide in A549, H460 and H1703 NSCLC cell lines. In the four combinations based on two NSCLC xenograft models and two chemotherapy, we also observed tumor regression at tolerated doses in vivo. Moreover, we identified a P53-dependent accelerated senescence response by M3814 following treatment with paclitaxel/etoposide. The present study provides a theoretical basis for the use of M3814 in combination with paclitaxel and etoposide in clinical practice, with hope to aid the optimization of NSCLC treatment.

很大一部分非小细胞肺癌 (NSCLC) 患者经历了与化疗相关的不良事件的累积，这激发了化疗增敏策略的设计。化疗药物引起的主要细胞毒性损伤是 DNA 双链断裂 (DSB)。因此可以想象，减弱 DNA 修复的 DNA 依赖性蛋白激酶 (DNA-PK) 抑制剂会增强化疗的抗肿瘤作用。本研究旨在系统评价新型 DNA-PK 抑制剂 M3814 与 NSCLC 化疗协同作用的疗效和安全性。我们发现人类 NSCLC 组织中 DNA-PK 的表达增加，这与预后不良有关。M3814 增强了紫杉醇和依托泊苷在 A549、H460 和 H1703 NSCLC 细胞系中的抗肿瘤作用。在体内。此外，我们在紫杉醇/依托泊苷治疗后发现了 M3814 的 P53 依赖性加速衰老反应。本研究为M3814联合紫杉醇和依托泊苷在临床上的应用提供了理论依据，希望有助于优化NSCLC的治疗。