Abstract Over 95% of pancreatic ductal adenocarcinomas (PDACs) harbor oncogenic KRAS mutations. Although recently developed KRAS inhibitors have demonstrated promising clinical activity, both intrinsic and adaptive resistance frequently occur. Understanding and overcoming these resistance mechanisms are therefore critical. We identified TGFβ and S100A4 as soluble factors that promote KRAS-targeted therapy resistance in PDAC models. Circulating macrophages within the tumor microenvironment (TME) contribute to this resistance by supplying tumor cells with abundant TGFβ and S100A4. These autocrine and paracrine signals enhance tumor cell lineage plasticity and stress adaptation. Importantly, we discovered that the nuclear factor NFAT5 mediates TGFβ-induced KRAS therapy resistance. NFAT5 forms a novel complex with SMAD3 and SMAD4, key transcription factors in the canonical TGFβ pathway, to activate S100A4 expression. Genetic and pharmacological inhibition of NFAT5 significantly impaired KRAS therapy resistance. Moreover, depletion of NFAT5 in non-cancer cells also reduced resistance, consistent with single-cell RNA-seq data showing high NFAT5 expression in multiple non-malignant cell types within the TME. Together, these findings reveal that NFAT5 promotes KRAS inhibitor resistance through both tumor cell–intrinsic and –extrinsic mechanisms, highlighting NFAT5 as a promising therapeutic target to overcome KRAS-targeted therapy resistance in PDAC. Citation Format: Daiyong Deng, Yuemeng Huang, Pingping Hou. NFAT5 regulates KRAS target therapy resistance in pancreatic cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr B019.
Deng et al. (2026) studied this question.