Sequential YAP1/FOSL1 silencing and epigenetic therapy to overcome stromal barriers in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive malignancy with poor therapeutic outcomes due to its desmoplastic tumor microenvironment (TME), hindering drug and activated immune cell penetration. Cancer-associated fibroblasts (CAFs) are central in supporting tumor growth and forming a protective stroma. We propose a novel dual-therapy targeting the Hippo/MAPK pathways and histone deacetylation, both involved in tumor progression, resistance, and stromal interactions, to overcome PDAC therapeutic resistance. We developed liposomal siRNA complexes (lipoplexes) to deliver siRNA targeting YAP1 and FOSL1, key transcription factors involved in stromal remodeling and tumor progression. Our strategy involves a sequential approach with initial YAP1/FOSL1 silencing, followed by combination chemotherapy with entinostat (a histone deacetylation inhibitor) and gemcitabine. We evaluated this approach in PDAC xenograft mouse models and 3D organoids, demonstrating that sequential YAP1/FOSL1 silencing enhanced the efficacy of subsequent chemotherapy by reducing stromal components and improving drug penetration. These findings suggest that targeting the Hippo/MAPK pathways, combined with epigenetic modulation, holds significant promise for improving PDAC treatment.

Keywords: Cancer-associated fibroblasts; Entinostat; Gemcitabine; Histone deacetilases; Lipoplexes; Organoids; Pancreatic cancer; Xenograft.