ArticleClinical cancer research : an official journal of the American Association for Cancer Research2025
Targeting KRAS Inhibitor-Resistant Pancreatic Cancer with an MUC1-C Antibody-Drug Conjugate.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- M1C is a druggable target for NSCLC KRAS G12C mutant tumors resistant to KRAS inhibitors.Oncogene · 2026Article
- Review
- M1C IS NECESSARY FOR DARAXONRASIB RESISTANCE OF NSCLC KRAS(G12C) MUTANT CELLS.bioRxiv : the preprint server for biology · 2026Article
- Distinct O-Linked Glycosylation Systems in Signaling and Immune Regulation.International journal of molecular sciences · 2026Review
- Clinically aggressive early-onset pancreatic ductal adenocarcinoma with KRAS wild-type status: A case report.Biomedical reports · 2026Article
- Immuno-cytotoxic convergence: integrating antibody‒drug conjugates and immunofusion proteins to overcome resistance in gastrointestinal cancers.Journal of hematology & oncology · 2026Review
- Evolution of the MUC1 gene in eutherian mammals as an adaptation responsible for the increasing incidence of cancer in humans.Biochimica et biophysica acta. Reviews on cancer · 2026Review
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21 authors.
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Abstract
purposeTreatment of pancreatic ductal adenocarcinoma (PDAC) has been advanced by the development of KRAS inhibitors. Despite this progress, PDAC invariably develop resistance to these agents through multiple mechanisms. In this study, we investigated the role of the oncogenic MUC1-C (M1C) protein in mediating the resistance of PDAC cells to KRAS inhibition. EXPERIMENTAL
designThree PDAC KRAS G12D-mutant cell lines, as well as patient-derived KRAS inhibitor-resistant organoids and patient-derived xenograft models, were investigated in these studies. An anti-M1C antibody-drug conjugate (ADC) was evaluated for in vitro and in vivo activity. Tumors from patients with PDAC were studied by single-cell RNA sequencing and IHC staining.
resultsThe MUC1 gene is upregulated in PDAC KRAS G12D-mutant tumors. We report that treatment of PDAC cells with the KRAS G12D inhibitor MRTX1133 is associated with the induction of the M1C protein. Mechanistically, KRAS G12D inhibition induces M1C by activation of an M1C/NF-κB p65 autoinductive pathway. Our results further demonstrate that M1C drives resistance to MRTX1133 by activating the inflammatory IFN type I pathway. Targeting M1C genetically and pharmacologically thereby reverses MRTX1133 resistance and is synergistic in combination with MRTX1133 treatment. Of translational significance, we demonstrate that an anti-M1C ADC is highly effective against MRTX1133-resistant PDAC KRAS G12D cell lines and patient-derived organoid and patient-derived xenograft models.
conclusionsThese findings demonstrate that M1C confers resistance of PDAC to KRAS G12D inhibition and identify M1C as a potential target for ADC treatment of patients with PDAC who are refractory to KRAS inhibitors.
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