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Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity
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Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity

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Prolonged KRAS-MAPK Inhibition Induces Interferon Signaling That Promotes Cell State Transition and Confers

Ashenafi Bulle1, Yali Chen1, Huaping Li1

  • 1Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.

Cancer Research
|April 20, 2026
PubMed

Insights

Acquired resistance in pancreatic cancer is driven by KRAS-MAPK inhibitors activating an interferon-TRIM22-NF-κB pathway, promoting EMT. Targeting TROP2 with antibody-drug conjugates offers a new strategy to overcome this drug resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Acquired resistance to KRAS-MAPK inhibitors is a major challenge in pancreatic ductal adenocarcinoma (PDAC) treatment.
  • Transcriptional plasticity and epithelial-to-mesenchymal transition (EMT) are implicated in the development of this resistance.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying KRAS-MAPK inhibitor resistance in PDAC.
  • To identify actionable vulnerabilities associated with drug resistance.

Main Methods:

  • Sustained KRAS-MAPK inhibition in PDAC models.
  • Network analysis to identify key regulatory molecules.
  • Mechanistic studies on TRIM22, IκBα, and NF-κB signaling.
  • Assessment of TROP2 expression.
  • Combination therapy studies using KRAS/ERK inhibitors and TROP2-directed antibody-drug conjugates in xenograft models.

Main Results:

  • KRAS-MAPK inhibition induced interferon and NF-κB signaling, promoting an EMT-like state and drug resistance.
  • TRIM22 was identified as a central regulator, driving IκBα degradation, sustained NF-κB activation, and EMT.
  • TRIM22 expression was regulated by IRF1 and IRF9.
  • TROP2 was upregulated in basal-like PDAC states and associated with EMT.
  • Combination therapy with TROP2-directed ADC and KRAS/ERK inhibitors significantly suppressed PDAC tumor growth.

Conclusions:

  • Prolonged KRAS-MAPK inhibition activates an interferon-TRIM22-NF-κB axis, leading to EMT and therapeutic resistance in PDAC.
  • TROP2 represents a clinically actionable vulnerability for overcoming acquired resistance in PDAC.

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