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

ABSTRACT:

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 i

SUBMITTER: Ozawa H 

PROVIDER: S-EPMC12703357 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature