Inhibition of Translesion DNA Synthesis Sensitizes BRCA-Deficient Ovarian Cancer to PARP Inhibitors.

Inhibiting translesion synthesis enhances PARP inhibitor effectiveness, preventing resistance in BRCA-deficient ovarian cancer by delaying tumor relapse and promoting sustained regression.

• Why it matters: Overcoming resistance to PARP inhibitors remains a major challenge in treating BRCA-mutated ovarian cancer, limiting long-term treatment success and patient outcomes.
• What they did: The study used genetic and pharmacological approaches to block TLS, particularly Polζ, in HR-deficient ovarian cancer cell lines, patient-derived organoids, and mouse models, assessing effects on replication stress and resistance.
• The result: TLS inhibition synergized with PARPi to increase tumor cell death, prevent BRCA2 reversion mutations, and delay or stop resistance development, suggesting TLS targeting as a promising strategy to improve therapy durability.