Abstract SY19-02: Exploiting replication gaps for cancer therapy

Abstract Synthetic lethality between loss of BRCA1 and inhibition of PARP1 defines a therapeutic vulnerability exploited by PARP inhibitors (PARPi), yet the replication-associated basis of this interaction remains incompletely understood. Our laboratory has identified replication gaps as a key determinant of PARPi sensitivity in BRCA-deficient cancer cells, but the mechanisms generating these gaps have remained unclear.Here, we show that defects in lagging-strand maturation contribute to the formation of replication gaps that sensitize cells to PARP inhibition. We find that positioning of the flap endonuclease FEN1 during DNA replication is dynamically regulated by BRCA1-, PARP1-, and 53BP1-associated processes at replication forks. Disruption of this regulatory network alters replication-associated PARP1 activity, promotes gap formation, and modulates cellular sensitivity to PARP or FEN1 inhibition.Together, these findings support a model in which replication gaps arising from defective lagging-strand processing represent an exploitable vulnerability in BRCA-deficient cancers. By linking replication maturation to therapeutic response, our work highlights replication gap biology as an emerging framework for developing strategies that exploit replication-associated vulnerabilities in cancer. Citation Format: Sharon B. Cantor, Hitha G. Nair, Min Peng, Sumeet Nayak, Nathan MacGilvary, Joseph Edmonds, Dohoon Kim. Exploiting replication gaps for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr SY19-02.