Emerging strategies for cancer therapy by ATR inhibitors

• Published in: Cancer science Vol. 114; no. 7; pp. 2709 - 2721
• Main Authors: Yano, Kimiyoshi, Shiotani, Bunsyo
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.07.2023; John Wiley and Sons Inc
• Subjects: Addictions; Apoptosis; Ataxia; ATR inhibitor; ATR kinase; biomarker; Cancer; Cancer therapies; cancer therapy; Cell cycle; Cell division; Cell survival; Clinical trials; Cyclin-dependent kinases; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA damage; DNA replication stress; Genomes; Genomic instability; Kinases; Phosphorylation; Proteins; Replication; replication stress tolerance; Review; Signal transduction; cancer therapy; biomarker; ATR inhibitor; ATR kinase; replication stress tolerance; DNA replication stress
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15845

DNA replication stress (RS) causes genomic instability and vulnerability in cancer cells. To counteract RS, cells have evolved various mechanisms involving the ATR kinase signaling pathway, which regulates origin firing, cell cycle checkpoints, and fork stabilization to secure the fidelity of replication. However, ATR signaling also alleviates RS to support cell survival by driving RS tolerance, thereby contributing to therapeutic resistance. Cancer cells harboring genetic mutations and other changes that disrupt normal DNA replication increase the risk of DNA damage and the levels of RS, conferring addiction to ATR activity for sustainable replication and susceptibility to therapeutic approaches using ATR inhibitors (ATRis). Therefore, clinical trials are currently being conducted to evaluate the efficacy of ATRis as monotherapies or in combination with other drugs and biomarkers. In this review, we discuss recent advances in the elucidation of the mechanisms by which ATR functions in the RS response and its therapeutic relevance when utilizing ATRis. Potential models of action of ataxia telangiectasia and Rad3‐related inhibitors (ATRis) depending on DNA replication stress (RS) levels. Cancer cells often harbor increased RS because of oncogene activation and/or DNA damage response defects and become RS tolerant by acquiring ATR‐mediated RS tolerance mechanisms, thereby conferring susceptibility to therapeutic approaches using ATRis. RS at levels over the threshold, induced by ATRis as monotherapies or in combination with other drugs, can lead to cell death through replication catastrophe and mitotic catastrophe.