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Chronic pancreatitis, a known risk factor for PDAC, elevates TGF\u03b2 levels in the tumor microenvironment (TME), promoting resistance to KRAS therapy. Mechanistically, TGF\u03b2 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, TGF\u03b2 stimulates PDAC cells to secrete CCL2, recruiting macrophages that contribute to KRAS bypass through paracrine S100A4. Our findings elucidate the role of TGF\u03b2 signaling in EMT-associated KRAS therapy resistance and identify NFAT5 as a druggable target. Targeting NFAT5 could disrupt this regulatory network, offering a potential avenue for preventing resistance in PDAC.<\/jats:p>","DOI":"10.1084\/jem.20240766","type":"journal-article","created":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T02:20:46Z","timestamp":1726798846000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["NFAT5 governs cellular plasticity-driven resistance to KRAS-targeted therapy in pancreatic cancer"],"prefix":"10.1084","volume":"221","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5899-9177","authenticated-orcid":true,"given":"Daiyong","family":"Deng","sequence":"first","affiliation":[{"name":"Rutgers University New Jersey Medical School 1 Department of Microbiology, Biochemistry and Molecular Genetics, , Newark, NJ,","place":["USA"]},{"name":"Center for Cell Signaling, Rutgers University New Jersey Medical School 2 , Newark, 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