Abstract 1705: MUC1-C is a target for antibody-drug conjugate treatment of MRTX1133-resistant KRAS G12D mutant pancreatic ductal adenocarcinomas

Abstract Background: The MUCIN 1 (MUC1) gene evolved in mammals to protect barrier tissues from biotic and abiotic insults. MUC1 encodes a transmembrane MUC1-C subunit that is activated in response to the loss of homeostasis and promotes proliferative, inflammatory, and remodeling responses necessary for wound repair. However, in contrast to its protective function, prolonged activation of MUC1-C by chronic inflammation drives cancer progression. In cancer cells, MUC1-C forms complexes with receptor tyrosine kinases (RTKs), such as EGFR, at the cell membrane, contributing to downstream RTK→RAS signaling pathways. Previous research identified MUC1-C addiction in KRAS G12D mutant pancreatic ductal adenocarcinoma (PDAC) cells, against which there are limited therapeutic options. Treatment of KRAS G12D mutant PDACs has been advanced by development of the MRTX1133 inhibitor; however, resistance to this agent invariably occurs by unclear mechanisms. Results: We report that treatment of PDAC KRAS G12D cells with the MRTX1133 inhibitor is associated with marked induction of cell surface MUC1-C expression. Our results demonstrate that MRTX1133 activates an inflammatory MUC1-C/NF-κB p65 auto-inductive pathway. We further demonstrate that MRTX1133-induced MUC1-C/NF-κB signaling (i) regulates the gasdermin E (GASDME) pore-forming protein that paradoxically protects PDAC cells from pyroptosis, (ii) drives ZEB1 and the epithelial-mesenchymal transition (EMT), and (iii) is necessary for MRTX1133 resistance. These results indicate that MUC1-C is a target for the treatment of MRTX1133 resistant PDAC tumors. There are presently no effective antibody-drug conjugates (ADCs) for PDAC treatment. In extending our results, we show that an anti-MUC1-C ADC is highly effective against MRTX1133-resistant PDAC KRAS G12D cells and that targeting MUC1-C with the ADC is synergistic with MRTX1133 in vitro. We also demonstrate that the anti-MUC1-C ADC inhibits growth of PDAC MRTX1133 resistant tumor xenografts and PDX models. Conclusions: These findings indicate that MUC1-C confers resistance of PDAC KRAS G12D mutant cells to MRTX1133 and identify MUC1-C as a target for ADC treatment of patients refractory to MRTX1133 treatment. Citation Format: Hiroki Ozawa, Keisuke Shigeta, Shinkichi Takamori, Atrayee Bhattacharya, Donald Kufe. MUC1-C is a target for antibody-drug conjugate treatment of MRTX1133-resistant KRAS G12D mutant pancreatic ductal adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1705.