Replication stress in cancer: origins, consequences and therapeutic opportunities.

Replication stress in cancer is linked to genomic instability and tumor progression, with ATR-CHK1 pathway playing a key role in preventing catastrophic genome fragmentation.

• Why it matters: Understanding the origins and consequences of replication stress is crucial because it drives tumor evolution and heterogeneity, creating potential vulnerabilities for targeted therapy.
• What they did: The authors review molecular mechanisms of replication fork stabilization and restart, and discuss therapeutic strategies including ATR, CHK1, WEE1 inhibitors, and synthetic lethal approaches like PARP inhibition and WRN targeting, based on 16 clinical and preclinical studies.
• The result: Targeting replication stress response pathways offers promising avenues for precision oncology, exploiting tumor-specific dependencies and vulnerabilities created by chronic, sublethal replication stress.