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

  • Cancer Res. 2026 Jul 2;86(13):3270-3286. doi: 10.1158/0008-5472.CAN-25-4114.
Ashenafi Bulle  1 ,  Yali Chen  1 ,  Huaping Li  1 ,  Timothy Hung-Po Chen  1 ,  Iftikhar Ali Khawar  1 ,  Lin Li  1 ,  Yu Wang  1 ,  Peng Liu  1  2 ,  Vikas Kumar Somani  1 ,  Richard Kurupi  1 ,  Yutong Geng  1 ,  Ofejiro Blessing Pereye  1 ,  Sapana Bansod  1 ,  Son B Le  3 ,  Marianna B Ruzinova  4 ,  David D Tran  3 ,  Kian-Huat Lim  1
Affiliations
  • 1. Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
  • 2. Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China.
  • 3. Division of Neuro-Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
  • 4. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
PMID: 42008116 DOI: 10.1158/0008-5472.CAN-25-4114
Abstract

Acquired resistance limits the therapeutic efficacy of KRAS-MAPK inhibitors in pancreatic ductal adenocarcinoma (PDAC). As transcriptional plasticity and epithelial-to-mesenchymal transition (EMT) have been implicated in resistance, we sought to study the molecular mechanisms driving these changes to uncover actionable vulnerabilities. Sustained KRAS-MAPK inhibition induced interferon (IFN) and NF-κB signaling and promoted cell state change mimicking an EMT state associated with drug resistance. Network analysis identified the IFN-inducible E3 ubiquitin Ligase TRIM22 as a central regulator of this response. Mechanistically, TRIM22 promoted proteasomal degradation of IκBα, resulting in sustained NF-κB and EMT program activation that coincided with a basal-like transcriptional cell state. TRIM22 expression was driven by IRF1 and IRF9 following relief of ERK-mediated transcriptional repression during pathway inhibition. EMT induction was accompanied by marked upregulation of TROP2 (TACSTD2), an NF-κB target gene enriched in basal-like PDAC cell states. Combining TROP2-directed antibody-drug conjugate sacituzumab govitecan with KRAS or ERK inhibitors significantly suppressed PDAC tumor growth in xenograft models. Overall, prolonged KRAS-MAPK inhibition activates an IFN-TRIM22-NF-κB axis that drives EMT and therapeutic resistance in PDAC, while revealing TROP2 as a clinically actionable vulnerability to overcome acquired resistance.

Significance: TRIM22 drives interferon-induced EMT and NF-κB-dependent TROP2 upregulation to drive resistance to KRAS-MAPK inhibition in pancreatic Cancer, which can be overcome by combining sacituzumab govitecan with KRAS-MAPK inhibitors.

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