胰腺导管腺癌 (PDAC) 对 KRAS 治疗的耐药性涉及细胞可塑性，特别是上皮间质转化 (EMT)，这对有效靶向提出了挑战。慢性胰腺炎是 PDAC 的一个已知危险因素，它会提高肿瘤微环境 (TME) 中的 TGFβ 水平，从而促进对 KRAS 治疗的耐药性。从机制上讲，TGFβ诱导由 SMAD3、SMAD4 和核因子 NFAT5 组成的新型蛋白质复合物的形成，通过激活 S100A4 等关键介质来触发 EMT 和耐药性。抑制 NFAT5 可减弱胰腺炎诱导的对 KRAS 抑制的抵抗力并延长小鼠的存活时间。此外，TGFβ 刺激 PDAC 细胞分泌 CCL2，招募巨噬细胞，通过旁分泌 S100A4 促进 KRAS 旁路。我们的研究结果阐明了 TGFβ 信号传导在 EMT 相关 KRAS 治疗耐药中的作用，并将 NFAT5 确定为可药物靶点。以 NFAT5 为目标可能会破坏这一监管网络，为预防 PDAC 耐药性提供潜在途径。© 2024 Deng 等人。

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 S100A4. Our findings elucidate the role of TGFβ 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.© 2024 Deng et al.