Inhibition of the ATR-DNAPKcs-RB axis drives G1/S-phase transition and sensitizes triple-negative breast cancer (TNBC) to DNA holliday junctions

• Published in: Biochemical pharmacology 2024-07, Vol.225, p.116310, Article 116310
• Main Authors: Hu, Yue-miao, Liu, Xue-cun, Hu, Lei, Dong, Zhi-wen, Yao, Hong-ying, Wang, Ying-jie, Zhao, Wen-jing, Xiang, Yu-ke, Liu, Yi, Wang, Hong-bo, Yin, Qi-kun
• Format: Article
• Language: English
• Subjects: Ataxia Telangiectasia and Rad3-related protein; Cell cycle; DNA Holliday junction; Retinoblastoma; Triple Negative Breast Cancer
• ISSN: 0006-2952; 1873-2968; 1873-2968
• DOI: 10.1016/j.bcp.2024.116310

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.