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
Summary
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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