Related Experiment Video

Updated: Jun 9, 2025

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
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NFAT5 governs cellular plasticity-driven resistance to KRAS-targeted therapy in pancreatic cancer

Daiyong Deng1,2, Habeebunnisa Begum1,2, Tong Liu1,2

  • 1Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University New Jersey Medical School, Newark, NJ, USA.

The Journal of Experimental Medicine
|October 21, 2024
PubMed

Insights

Chronic pancreatitis promotes KRAS therapy resistance in pancreatic cancer via TGFβ-induced EMT. Targeting the nuclear factor NFAT5 (nuclear factor of activated T-cells 5) can overcome this resistance and improve survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) exhibits resistance to KRAS therapy, often linked to cellular plasticity like epithelial-to-mesenchymal transition (EMT).
  • Chronic pancreatitis, a risk factor for PDAC, increases transforming growth factor beta (TGFβ) in the tumor microenvironment (TME), contributing to therapy resistance.

Purpose of the Study:

  • To investigate the molecular mechanisms by which TGFβ signaling drives KRAS therapy resistance in PDAC.
  • To identify novel therapeutic targets for overcoming resistance in PDAC.

Main Methods:

  • Analysis of protein complexes involved in TGFβ signaling.
  • Inhibition of NFAT5 in preclinical models.
  • Assessment of macrophage recruitment and function.

Main Results:

  • TGFβ induces a SMAD3/SMAD4/NFAT5 complex, promoting EMT and resistance via S100A4 activation.
  • NFAT5 inhibition reduced pancreatitis-induced KRAS resistance and improved survival in mice.
  • TGFβ-stimulated CCL2 secretion recruited macrophages, contributing to KRAS bypass.

Conclusions:

  • TGFβ signaling plays a critical role in EMT-driven KRAS therapy resistance in PDAC.
  • NFAT5 is a druggable target that can disrupt the resistance network, offering a potential strategy for enhancing PDAC treatment.

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