靶向 DNA 损伤反应 (DDR) 是肿瘤治疗中一种很有前途的策略，因为大多数肿瘤细胞由于其修复缺陷而对过度损伤敏感。共济失调毛细血管扩张突变和RAD3相关蛋白（ATR）是一种损伤反应信号转导传感器，其在肿瘤细胞中的治疗潜力需要精确研究。在此，我们确定了 ATR 抑制剂可以靶向的新轴，以减少 DNA 依赖性蛋白激酶催化亚基 (DNAPKcs)、下调视网膜母细胞瘤 (RB) 的表达并驱动 G1/S 相转变。在此过程中组装的四路 DNA 霍利迪连接体 (FJ) 可以触发 S 期停滞，并诱导 RB 阳性三阴性乳腺癌 (TNBC) 细胞致命的染色体损伤。此外，当同源重组修复（HRR）受到抑制时，这些未修复的连接也会对 RB 缺陷的 TNBC 细胞产生毒性作用。这项研究提出了一种针对 DDR 治疗 TNBC 的精准策略，并扩展了我们对 ATR 和 HJ 在肿瘤治疗中的理解。版权所有 © 2024。由 Elsevier Inc. 出版。

Targeting the DNA damage response (DDR) is a promising strategy in oncotherapy, as most tumor cells are sensitive to excess damage due to their repair defects. Ataxia telangiectasia mutated and RAD3-related protein (ATR) is a damage response signal transduction sensor, and its therapeutic potential in tumor cells needs to be precisely investigated. Herein, we identified a new axis that could be targeted by ATR inhibitors to decrease the DNA-dependent protein kinase catalytic subunit (DNAPKcs), downregulate the expression of the retinoblastoma (RB), and drive G1/S-phase transition. Four-way DNA Holliday junctions (FJs) assembled in this process could trigger S-phase arrest and induce lethal chromosome damage in RB-positive triple-negative breast cancer (TNBC) cells. Furthermore, these unrepaired junctions also exerted toxic effects to RB-deficient TNBC cells when the homologous recombination repair (HRR) was inhibited. This study proposes a precise strategy for treating TNBC by targeting the DDR and extends our understanding of ATR and HJ in tumor treatment.Copyright © 2024. Published by Elsevier Inc.