Faculty, Staff and Student Publications

Language

English

Publication Date

12-1-2025

Journal

Cancer Research

DOI

10.1158/0008-5472.CAN-25-2024

PMID

40966362

PMCID

PMC12515478

PubMedCentral® Posted Date

10-13-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

KRASG12C inhibitors (G12Ci) have produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the function of KRASG12C and possible G12Ci bypass mechanisms, we developed an autochthonous KRASG12C-driven PDAC model. Compared to the classical KRASG12D PDAC model, the G12C model exhibits slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRASG12C tumors produced modest impact despite stimulating a ‘hot’ tumor immune microenvironment. Immunoprofiling revealed that CD24, a ‘don’t eat me’ signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRASG12D-driven PDAC. Together, this study reveals common and distinct oncogenic KRAS allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC.

Keywords

CD24 Antigen, Proto-Oncogene Proteins p21(ras), Pancreatic Neoplasms, Animals, Mice, Humans, Carcinoma, Pancreatic Ductal, Tumor Microenvironment, Cell Line, Tumor, Xenograft Model Antitumor Assays, Signal Transduction, Mice, Transgenic, Mutation

Published Open-Access

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