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PURPOSE: Treatment 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 DESIGN: Three 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.RESULTS: The 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.CONCLUSIONS: These 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.