Faculty, Staff and Student Publications

Language

English

Publication Date

9-3-2025

Journal

Science Translational Medicine

DOI

10.1126/scitranslmed.adt5511

PMID

40901924

PMCID

PMC12742855

PubMedCentral® Posted Date

12-27-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

KRAS is among the most frequently mutated oncogenes in cancer, and for decades, efforts at pharmacological blockade of its function in solid cancers have been unsuccessful. A notable advance in this endeavor is the recent development of small molecule KRAS inhibitors, which enable direct targeting of the mutant oncoprotein. Here, we comprehensively evaluate the pre-clinical efficacy of BI-2493 a panKRASi, a first-in-class allele agnostic mutant KRAS inhibitor, in pancreatic ductal adenocarcinoma (PDAC). We report effective tumor growth suppression across a broad range of models, including cell lines, patient-derived xenografts (PDXs), syngeneic orthotopic models, and prolonged survival in genetically engineered mouse models. Overall, transcriptomic, proteomic, and phospho-proteomic profiling of panKRASi-treated models confirmed RAS pathway inhibition along with upregulation of LKB1/AMPK targets. In panKRASi-treated immune-replete models, we observed increased intratumoral CD8+ effector T cells and decreased infiltration of myeloid cells, along with remodeling of the tumor microenvironment (TME), enabling responses to immune checkpoint blockade. In the long-term, emergence of resistance to panKRASi monotherapy was associated with increased YAP signaling within tumor cells, and enhanced expression of immune checkpoints within the TME that impede effective T cell function. Our multifaceted approach identified potential combinatorial approaches for generating sustained responses to panKRASi.

Keywords

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

Published Open-Access

yes

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