NFAT5 governs cellular plasticity-driven resistance to KRAS-targeted therapy in pancreatic cancer.

ABSTRACT: Resistance to KRAS therapy in pancreatic ductal adenocarcinoma (PDAC) involves cellular plasticity, particularly the epithelial-to-mesenchymal transition (EMT), which poses challenges for effective targeting. Chronic pancreatitis, a known risk factor for PDAC, elevates TGFβ levels in the tumor microenvironment (TME), promoting resistance to KRAS therapy. Mechanistically, TGFβ induces the formation of a novel protein complex composed of SMAD3, SMAD4, and the nuclear factor NFAT5, triggering EMT and resistance by activating key mediators such as S100A4. Inhibiting NFAT5 attenuates pancreatitis-induced resistance to KRAS inhibition and extends mouse survival. Additionally, TGFβ stimulates PDAC cells to secrete CCL2, recruiting macrophages that contribute to KRAS bypass through paracrine S100A

SUBMITTER: Deng D 

PROVIDER: S-EPMC11497412 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature