Targeting Genome Maintenance Defects of Cancers Using Chain-Terminating Nucleoside Analogs

Conventional cancer therapies, including radiation therapy and chemotherapy, rely on inflicting DNA damage, yet they inevitably affect normal cells, leading to severe adverse effects. The advent of precision chemotherapy exploiting tumor-specific DNA repair defects has validated the effectiveness of this approach. The first successful example is PARP inhibitors, which selectively kill homologous recombination (HR) defective cancers, such as familial breast cancer possessing HR deficiency due to BRCA gene mutations. However, the broader landscape of DNA maintenance-including DNA replication, repair, and checkpoint pathways-harbors numerous mutations in tumors that remain untargeted. Here, we propose repurposing chain-terminating nucleoside analogs (CTNAs) to target such cancers' vulnerabilities. CTNAs, long utilized as anti-cancers and anti-viral drugs, inhibit replication and thereby suppress growth, but their activity has never been systematically aligned with specific cancer mutations associated with DNA maintenance defects. Based on our recent studies, we demonstrate that CTNAs elicit synthetic lethality in cells deficient for distinct DNA maintenance systems, amplifying replication stress, leading to cell death. We highlight the spectrum of CTNA-induced lesions and repair pathways required for cellular tolerance. This framework presents a versatile "repair-defect-guided" chemotherapy that expands the clinical utility of CTNAs and improves therapeutic effect by reducing side effects.