Abstract 7138: Acquired saruparib (AZD5305) resistance in BRCA1-deficient triple negative breast cancer is vulnerable to DNA damage response-targeted therapeutics

Abstract The development of poly (ADP)-ribose polymerase (PARP) inhibitors (PARPi) for the synthetic lethal killing of BRCA1/2-deficient cancers revolutionized BRCA1/2-deficient patient outlook and survival. PARPi are now commonly used to treat BRCA1/2-deficient or homologous recombination (HR)-deficient breast, ovarian, prostate, and pancreatic cancers. Despite this clinical success, 30-40% of BRCA1/2-deficient patients do not respond to PARPi and the vast majority that do initially respond, ultimately develop PARPi resistance. This represents a major challenge limiting the clinical impact of PARPi treatment. Understanding PARPi resistance mechanisms is essential for developing better treatment strategies for intrinsic and acquired PARPi-resistant cancers. Recent efforts to better treat BRCA1/2-deficient cancers and combat PARPi resistance led to the development of saruparib (AZD5305), a PARP1-specific inhibitor with significantly improved safety profiles due to limited off-target inhibition of other PARP family members and hence reduced toxicity. Saruparib is currently undergoing phase 3 clinical trials and is anticipated to be the standard of care PARPi for BRCA1/2- and HR-deficient cancer patients. We have generated 5 saruparib-resistant (SR) cell lines from parental BRCA1-deficient MDA-MB-436 triple negative breast cancer (TNBC) cells that are 1000-fold resistant to saruparib but exhibit differential sensitivity to other nonspecific clinical PARPi. SR cell lines exhibit altered inhibition of cellular PARP activity and PARP trapping in response to saruparib and the nonspecific PARPi talazoparib. Whole genome sequencing identified PARP1 active site mutations in each SR cell line, and in vitro reconstitution of these mutants suggests that they are driving resistance to saruparib and altered sensitivity to other nonspecific clinical PARPi. Importantly, despite acquired saruparib resistance, SR cell lines retain sensitivity to other DNA damage response targeted therapeutics. Collectively, this work characterizes what we believe to be the first BRCA1-deficient models of acquired saruparib resistance and uncovers vulnerabilities that may inform rational combination strategies and novel therapeutic approaches for patients who progress on saruparib in the clinic. Citation Format: Matthew R. Jordan, Pamela S. VanderVere-Carozza, Jessica Lynn Kersey, Katherine Pawelczak, John J. Turchi. Acquired saruparib (AZD5305) resistance in BRCA1-deficient triple negative breast cancer is vulnerable to DNA damage response-targeted therapeutics abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7138.