Targeting KRAS Inhibitor-Resistant Pancreatic Cancer with an MUC1-C Antibody-Drug Conjugate

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Pancreatic ductal adenocarcinoma (PDAC) treatment is improving with KRAS inhibitors.
• However, PDAC frequently develops resistance to these therapies through various mechanisms.
• The role of the MUC1-C (M1C) protein in mediating this resistance is not fully understood.

Purpose of the Study:

• To investigate the role of the oncogenic MUC1-C (M1C) protein in mediating resistance of PDAC cells to KRAS inhibition.
• To evaluate the efficacy of targeting M1C in overcoming KRAS inhibitor resistance in PDAC.
• To assess the therapeutic potential of an anti-M1C antibody-drug conjugate (ADC) in preclinical PDAC models.

Main Methods:

• Utilized KRAS G12D-mutant PDAC cell lines, patient-derived organoids, and xenograft models.
• Investigated the effect of KRAS G12D inhibitor MRTX1133 on M1C expression and downstream pathways.
• Assessed the efficacy of genetic and pharmacological M1C targeting, including an anti-M1C ADC, in vitro and in vivo.
• Analyzed patient tumor samples using single-cell RNA sequencing and IHC staining.

Main Results:

• MUC1 gene is upregulated in PDAC KRAS G12D-mutant tumors.
• KRAS G12D inhibition with MRTX1133 induces M1C expression via an M1C/NF-κB p65 autoinductive pathway.
• M1C activation of the IFN type I pathway drives resistance to MRTX1133.
• Targeting M1C reverses MRTX1133 resistance and shows synergistic effects when combined with MRTX1133.
• An anti-M1C ADC demonstrates high efficacy against MRTX1133-resistant PDAC models.

Conclusions:

• MUC1-C (M1C) confers resistance to KRAS G12D inhibition in PDAC.
• M1C is a potential therapeutic target for overcoming KRAS inhibitor resistance in PDAC.
• Anti-M1C ADCs represent a promising treatment strategy for patients with refractory PDAC.