YAP1 Inhibitors Enhance the Therapeutic Effect of Gemcitabine on PDCA by Inhibiting MSLN Expression, EMT, and Pancreatic Fibrosis

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with poor prognosis and limited response to gemcitabine-based chemotherapy. Chemoresistance in PDAC arises from both cancer-intrinsic mechanisms and extrinsic factors like stromal fibrosis. This study investigates the role of mesothelin (MSLN) and the YAP1 inhibitor TED-347 in modulating gemcitabine resistance. Elevated MSLN expression in PDAC correlates with advanced disease stages and poor prognosis. Mechanistically, MSLN promotes gemcitabine resistance by counteracting drug-induced apoptosis and upregulating ABCC1, a key drug efflux transporter. YAP1 transcriptionally activates MSLN by binding to its promoter, independent of the Canscript sequence. The YAP1 inhibitor TED-347 disrupts this interaction, reducing MSLN expression and suppressing PDAC cell migration, invasion, and epithelial-mesenchymal transition (EMT). In a mouse model, TED-347 combined with gemcitabine enhanced antitumor efficacy, reduced fibrosis, and increased gemcitabine sensitivity. Notably, TED-347 alleviated stromal fibrosis by inhibiting pancreatic stellate cell (PSC) activation, addressing a critical barrier to drug delivery. While gemcitabine itself induces fibrosis, TED-347 mitigates this effect, offering a dual therapeutic strategy. These findings highlight the YAP1-MSLN axis as a key driver of chemoresistance and fibrosis in PDAC, with TED-347 demonstrating potential to improve clinical outcomes by targeting both malignant and stromal components. This study provides a translational research framework for combining YAP1 inhibitors with chemotherapy to overcome resistance in PDAC.