Abstract IA-026: Gaps alone kill BRCA deficient cancer cells

Abstract

Abstract Defects in DNA repair and/or the protection of stalled DNA replication forks are thought to underlie the chemosensitivity of tumors deficient in the hereditary breast cancer genes, BRCA1 and BRCA2 (BRCA). Challenging this assumption, recent findings indicate that chemotherapies such as cisplatin used to treat BRCA-deficient tumors do not initially cause DNA double-strand-breaks (DSBs). Here, we show that single stranded DNA (ssDNA) replication gaps underlie the hypersensitivity of BRCA-deficient cancer, and we propose that defects in homologous recombination (HR) or fork protection (FP) do not. Specifically, in BRCA-deficient cells, ssDNA gaps develop because replication is not effectively restrained in response to stress. Gap suppression by either restoration of fork restraint or gap filling confers therapy resistance in tissue culture and BRCA patient tumors. In contrast, restored FP and HR can be uncoupled from therapy resistance when gaps are present. Moreover, we find that DSBs are not detected after therapy when apoptosis is inhibited, supporting a framework in which DSBs are not directly induced by genotoxic agents, but rather from cell death nucleases. Together, this data indicate that ssDNA replication gaps underlie the BRCA cancer phenotype, “BRCAness,” and we propose are fundamental to the mechanism-of-action of genotoxic chemotherapies. Citation Format: Sharon B. Cantor, Nicholas Panzarino. Gaps alone kill BRCA deficient cancer cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-026.