Inhibition of Focal Adhesion Restricts Chemoresistance in Pancreatic Cancer by Targeting SLC7A11 Mediated Ferroptosis

Abstract

Chemoresistance in pancreatic ductal adenocarcinoma (PDAC) is common and complex, accompanied with chemotherapy process. Gemcitabine-based chemotherapy regimens have shown limited antitumor effects for PDAC, and combination targets are urgently needed to restrict chemoresistance. We attempted to identify the candidate targets with gemcitabine (Gem) through scRNA-seq and bulk-seq analysis based on chemotherapy-treated and Gem-resistant (GR) samples, respectively. The mechanisms were investigated with experimental validation in vitro and in vivo preclinical PDAC models. We found that chemoresistance and evolution after chemotherapy of PDAC were associated with activation of focal adhesion signal. Mechanistically, the focal adhesion kinase (FAK) inhibitor (IN10018) could restrict chemoresistance to Gem of PDAC by targeting SLC7A11-mediated ferroptosis through PI3K-Akt signaling pathway. For tumor microenvironment, IN10018 reduced the abundance of mesenchymal components and enhanced CD8⁺ T cell infiltration.

Keywords: chemoresistance; ferroptosis; focal adhesion kinase; pancreatic cancer; scRNA‐seq.