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

J Exp Med. 2024 Nov 4;221(11):e20240766. doi: 10.1084/jem.20240766. Epub 2024 Oct 21.

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 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.

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal* / drug therapy
  • Carcinoma, Pancreatic Ductal* / genetics
  • Carcinoma, Pancreatic Ductal* / metabolism
  • Carcinoma, Pancreatic Ductal* / pathology
  • Cell Line, Tumor
  • Cell Plasticity
  • Drug Resistance, Neoplasm* / genetics
  • Epithelial-Mesenchymal Transition*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / metabolism
  • Pancreatic Neoplasms* / pathology
  • Proto-Oncogene Proteins p21(ras)* / genetics
  • Proto-Oncogene Proteins p21(ras)* / metabolism
  • S100 Calcium-Binding Protein A4
  • Signal Transduction
  • Smad3 Protein / metabolism
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • Transforming Growth Factor beta* / metabolism
  • Tumor Microenvironment

Substances

  • Proto-Oncogene Proteins p21(ras)
  • Transforming Growth Factor beta
  • Transcription Factors
  • KRAS protein, human
  • NFAT5 protein, human
  • Smad4 Protein
  • Smad3 Protein
  • S100a4 protein, mouse
  • S100 Calcium-Binding Protein A4