Abstract A062: Transcriptional and Chromatin Remodeling Programs Underlie Resistance to Gemcitabine and Nab-Paclitaxel in Pancreatic Cancer

Abstract Chemoresistance remains a major barrier to improving outcomes in pancreatic ductal adenocarcinoma (PDAC), particularly in response to frontline gemcitabine and nab-paclitaxel (GnP) therapy. We aimed to identify transcriptional drivers of acquired GnP resistance and evaluate their therapeutic potential in PDAC. Although GnP is a standard-of-care regimen, most preclinical models rely on monotherapy-based systems, limiting insight into combination-specific resistance mechanisms. To address this, we developed GnP-resistant (GPR) cell lines by continuously culturing six syngeneic mouse PDAC lines that span the epithelial-to-mesenchymal transition (EMT) spectrum using a clinically relevant 1:8 paclitaxel-to-gemcitabine ratio. Two lines served as EMT controls with EMT-loss via Snail1/Twist1 knockout or EMT-gain via E-cadherin knockout. The remaining four unmodified KPC lines exhibited stable, spontaneous EMT phenotypes. Parental GPR cell lines >10- to 30-fold increase in IC50 as compared to their parental counterparts. Stable resistance was established through serial passaging under continuous exposure to consistent drug concentrations of gemcitabine paclitaxel. To assess whether resistance persisted in vivo, GPR and parental cells were orthotopically implanted into the pancreas of immunocompetent C57BL/6 mice. Upon palpable tumor formation, mice were treated with gemcitabine and nab-paclitaxel twice weekly. GnP significantly extended survival in mice bearing parental tumors (median >60 days), whereas those with GPR-derived tumors showed reduced survival (25–30 days), like vehicle-treated controls, demonstrating that acquired resistance negated GnP efficacy in vivo. To uncover molecular mechanisms of resistance, we performed bulk RNA sequencing on all six matched parental-GPR pairs. Transcriptomic analysis revealed shared changes in gene expression across GPR lines, including activation of proliferative pathways and factors involved in transcriptional regulation and chromatin remodeling. These resistance-associated programs were further validated in GnP-treated tumors by immunohistochemistry and RNA sequencing. Analysis of patient datasets showed that elevated expression of chromatin remodeling factors was associated with poor prognosis in PDAC, underscoring their potential clinical relevance. Future studies will focus on defining chromatin-based mechanisms by which transcriptional reprogramming supports resistance to combination chemotherapy and identifying targetable epigenetic vulnerabilities in treatment-refractory PDAC. Citation Format: Meet Patel, Richard Laube, Ayushi Mandloi, Jace Baines, Robert S. Welner, Julienne L. Carstens. Transcriptional and Chromatin Remodeling Programs Underlie Resistance to Gemcitabine and Nab-Paclitaxel in Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A062.