Abstract
Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer characterized by the presence of mutations in homologous recombination (HR) repair genes, including BRCA1 and BRCA2, in approximately 20% of diagnosed cases. 53BP1 (tumor protein p53 binding protein 1) nucleates the anti-end resection machinery at DNA double strand break (DSB)s thereby countering BRCA1 activity. Importantly, BRCA1-deficient PDACs that are typically sensitive to poly-ADP ribose polymerase inhibitors (PARPi) become resistant in the absence of 53BP1. Here, we demonstrate that loss of 53BP1 results in enhanced DNA end-resection, increased micronuclei, and cytoplasmic dsDNA, leading to activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, activating pro-inflammatory signaling. This not only enhances CD8+ T cell infiltration but also activates macrophages and natural killer (NK) cells culminating in tumor growth inhibition. Loss of 53BP1 correlates with response to immune checkpoint blockade (ICB) and improved overall survival. Finally, BRCA1-deficient tumors that develop resistance to PARPi due to the loss of 53BP1 are susceptible to ICB. Taken together, our findings provide a rationale for combining PARPi with ICB to overcome PARPi-resistance in BRCA1-deficient pancreatic cancers. Citation Format: Jeffrey Patterson-Fortin, Yajie Sun, Sen Han, Zhe Li, Zuzanna Nowicka, Yuna Hirohashi, Susan Kilgas, Jae Kyo Yi, Alexander Spektor, Wojciech Fendler, Panagiotis Konstantinopoulos, Alan D. D'Andrea, Dipanjan Chowdhury. 53BP1 loss mediated PARP inhibitor resistance in BRCA1-deficient pancreatic cancer is overcome with immune checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A015.
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