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Targeting KRAS Inhibitor-Resistant Pancreatic Cancer with an MUC1-C Antibody-Drug Conjugate
Hiroki Ozawa1, Kazuki Takahashi1,2, Tomoki Motegi3
1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
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.
Insights
Pancreatic cancer (PDAC) develops resistance to KRAS inhibitors via the MUC1-C (M1C) protein. Targeting M1C with an antibody-drug conjugate (ADC) overcomes this resistance, offering a new treatment strategy for PDAC patients.
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.
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