DNA Damage Response and Its Inhibitors: Current Perspectives and Future Directions
ZHENG Xueyi, XIE Dan*, CAI Muyan*
The DDR (DNA damage response) is an essential cellular mechanism that detects and repairs DNA lesions to maintain genomic stability. Dysregulation of DDR pathways is frequently observed in human tumors, leading to increased genomic instability and promoting tumor progression. Consequently, targeting DDR mechanisms has emerged as a promising therapeutic strategy in oncology. This review provides an overview of the major DDR pathways, highlighting the roles of key proteins involved in various DDR processes. A detailed understanding of these molecular mechanisms has paved the way for the development of targeted antitumor agents, including inhibitors of PARP1, ATM, ATR, CHK1, CHK2, DNA-PK, and WEE1. Additionally, the significant challenges in the development of DDR inhibitors are examined, including tumor microenvironment heterogeneity, resistance mechanisms, issues with selectivity and toxicity, and the complexities associated with clinical trial design. Finally, future directions and emerging strategies to improve DDR-targeted therapies are discussed. These strategies include biomarker-driven precision medicine, novel combination therapies, advanced drug delivery systems, and the potential application of artificial intelligence to optimize treatment outcomes.
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