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

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

  • Biochem Pharmacol. 2024 Jul:225:116310. doi: 10.1016/j.bcp.2024.116310.
Yue-Miao Hu 1,  Xue-Cun Liu 1,  Lei Hu 1,  Zhi-Wen Dong 2,  Hong-Ying Yao 1,  Ying-Jie Wang 1,  Wen-Jing Zhao 1,  Yu-Ke Xiang 3,  Yi Liu 4,  Hong-Bo Wang 5,  Qi-Kun Yin 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Basic Science Research Center Base (Pharmaceutical Science), Yantai University, Yantai 264005, China.
  • 2 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Basic Science Research Center Base (Pharmaceutical Science), Yantai University, Yantai 264005, China; Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, China.
  • 3 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
  • 4 School of Chemistry and Chemical Engineering, Yantai University, Yantai 264005, China.
  • 5 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Basic Science Research Center Base (Pharmaceutical Science), Yantai University, Yantai 264005, China. Electronic address: hongbowang@ytu.edu.cn.
  • 6 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Basic Science Research Center Base (Pharmaceutical Science), Yantai University, Yantai 264005, China. Electronic address: qkyin@ytu.edu.cn.
PMID: 38788960 DOI: 10.1016/j.bcp.2024.116310
Abstract

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.

Keywords

Ataxia Telangiectasia and Rad3-related protein; Cell cycle; DNA Holliday junction; Retinoblastoma; Triple Negative Breast Cancer.

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