Abstract 434: Synergistic suppression of gemcitabine resistance in PDAC by targeting STAT3 and ABCB11

Abstract Gemcitabine resistance is a critical challenge in treating pancreatic ductal adenocarcinoma (PDAC). STAT3 is implicated in tumor progression and chemotherapy resistance. This study investigates the role of STAT3 in gemcitabine-resistant PDAC and evaluates the potential of a STAT3 inhibitor (napabucasin) to enhance gemcitabine efficacy. Gemcitabine-resistant PDAC cells were developed via long-term in vitro culture and in vivo xenograft models. The expression of STAT3 and its phosphorylated form (p-STAT3) was analyzed in resistant cells. Cytotoxicity assays evaluated the sensitivity of resistant and non-resistant PDAC cells to gemcitabine, napabucasin, and an EGFR inhibitor (gefitinib). RNA sequencing revealed upregulation of ABCB11, correlating with p-STAT3 levels, suggesting STAT3-driven multidrug resistance. Combination therapies were assessed in vitro using colony formation assays and in vivo using a PDAC xenograft mouse model treated with gemcitabine, napabucasin, and/or the ABCB11 inhibitor glibenclamide. Gemcitabine-resistant PDAC cells (BxPC3-GR and BxPC3-T1-GR) exhibited elevated STAT3 and p-STAT3 levels. Cytotoxicity assays demonstrated resistance to gemcitabine and gefitinib but increased sensitivity to napabucasin. Combination treatment with gemcitabine and napabucasin significantly suppressed colony formation in vitro. In vivo, combining gemcitabine with napabucasin and glibenclamide led to significant tumor growth inhibition in gemcitabine-resistant PDAC xenografts. The combination of gemcitabine, napabucasin, and glibenclamide synergistically suppresses tumor growth in resistant models, highlighting a potential therapeutic strategy to overcome gemcitabine resistance. Further studies are warranted to optimize combination therapies for clinical application. Citation Format: Tai-Lin Chen, Chi-Wei Chen. Synergistic suppression of gemcitabine resistance in PDAC by targeting STAT3 and ABCB11. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 434.