Abstract B066: Convergent cell-state programs characterize BRCA2 -reversion-independent resistance in pancreatic cancer
Abstract
Most patients with pancreatic ductal adenocarcinoma (PDAC) present with advanced-stage disease, for which systemic therapy is the mainstay, highlighting the need to identify therapeutically vulnerable molecular tumor subgroups. Homologous recombination deficiency (HRD), arising from germline or somatic alterations in up to 20% of PDACs, confers sensitivity to platinum chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi). However, acquired resistance frequently develops and remains poorly understood. We modeled resistance using patient-derived xenografts from two PDACs harboring pathogenic germline BRCA2 variants (c.5946delT & c.3167_3171delAAAA), representing experimental and clinical platinum/PARPi resistance. Whole-genome sequencing confirmed the absence of BRCA2 reversion mutations. From a 42-mouse trial, 11 sensitive and resistant tumors exposed to vehicle, cisplatin, or talazoparib underwent paired single-cell RNA and chromatin-accessibility profiling. Matched pre- and post-treatment tumors from 5 patients with pathogenic germline BRCA2 variants underwent whole-transcriptome spatial profiling. Findings were assessed in bulk transcriptomes from 138 primary and 163 metastatic PDACs spanning HRD and HR-proficient (HRP) disease. Separate consensus non-negative matrix factorization analyses of 42,765 cells identified 6 shared metaprograms: cell stress, MYC-plus-adhesion, translation, hypoxia, glycosylation, and epithelial-mesenchymal transition. Cell-stress and MYC-plus-adhesion programs, both previously linked to aggressive PDAC biology and adverse clinical outcomes, were enriched in resistant populations. Pseudotime analyses were consistent with expansion of basal-like states and enrichment of translation, squamoid, and cell-stress programs along sensitivity-to-resistance trajectories. Integrated analysis revealed concordant transcription-factor expression and motif accessibility, with HES1, ATF3, and JUN activity enriched in resistant cells. Spatial profiling confirmed colocalization of the 6 metaprograms and associations between aggressive programs and basal-like regions in several post-treatment tumors. Across 301 independent PDACs, each O28-derived signature correlated with its independently derived Q70 counterpart, further supporting external reproducibility. In an exploratory humanized BRCA2-mutated resistant-tumor model, the greatest CD8+ T-cell infiltration was observed with olaparib plus pembrolizumab. Together, these findings identify convergent transcriptional and epigenetic cell states associated with BRCA2-reversion-independent platinum/PARPi resistance in PDAC and suggest candidate transcriptional regulators for future functional investigation. Their reproducibility in paired human tumors and independent HRD and HR-proficient PDAC cohorts supports their broader biological and clinical relevance. Joan Miguel Romero, Yifan Wang, Edward Shanbedi, James Vafiadis, Ruomeng Fang, Hellen Kuasne, Adrien Osakwe, Alicia Gomez Mendez, Alain Pacis, Anne-Marie Fortier, Ashot Harutyunyan, Matthew G Annis, Yue Li, Adeline Cuggia, Peter M. Siegel, Gun Ho Jang, Amy Zhang, Julie Wilson, Faiyaz Notta, Robert Grant, Steven Gallinger, Morag Park, George Zogopoulos. Convergent cell-state programs characterize BRCA2-reversion-independent resistance in pancreatic cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B066.