An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer

<i>KRAS</i> 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 evaluated the preclinical efficacy of BI-2493, a first-in-class allele-agnostic mutant-KRAS inhibitor (panKRASi), in pancreatic ductal adenocarcinoma (PDAC). We report effective tumor growth suppression across a broad range of models, including cell lines, patient-derived xenografts (PDXs), and syngeneic orthotopic models, and prolonged survival in genetically engineered mouse models. Overall, transcriptomic, proteomic, and phosphoproteomic profiling of panKRASi-treated models confirmed RAS pathway inhibition along with up-regulation of LKB1/AMPK (liver kinase B1/AMP-activated protein kinase) targets. In panKRASi-treated immune-replete models, we observed increased intratumoral CD8<sup>+</sup> 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 in the TME that impede effective T cell function. Our multifaceted approach identified potential combinatorial approaches for generating sustained responses to panKRASi.

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Publication Details

Journal
Science Translational Medicine
Published
2025-09-03
DOI
https://doi.org/10.1126/scitranslmed.adt5511
Citations
4
Primary Topic
Phagocytosis and Immune Regulation
Type
article
Field-Weighted Citation Impact
3.19
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article

An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer

Raghu Kalluri, Clint A. Stalnecker, Melissa M. Ronan, David H. Peng et al.
4 citations
Science Translational Medicine
Phagocytosis and Immune Regulation
3.19
article

An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer

Raghu Kalluri, Clint A. Stalnecker, Melissa M. Ronan, David H. Peng, Christopher P. Vellano, Nathaniel G. Yee, Francesca Paradiso, Jörg F. Rippmann, Andrew S. Boghossian, Jesse Lipp, Martin Aichinger, Fredrik I. Thege, Kathleen M. McAndrews, Charles Deckard, Kimal Rajapakshe, Dorothea Rudolph, Antonio Tedeschi, Anirban Maitra, Vanessa Chandler, Artem V. Artemov, Linghua Wang, Jennifer A. Roth, Valerie L. Herrmann, Benson Chellakkan Selvanesan, Amari M. Sockwell, Laura Pisarsky, Florian Ebner, John Edward Park, Paola A. Guerrero, Channing J. Der, Timothy P. Heffernan, Matthew G. Rees, Hikaru Sugimoto, M.R. Williams, Krishnan K. Mahadevan, Otmar Schaaf, Danielle Wills, Hany A. Omar, Michelle L. Kirtley, Yunhe Liu, Phương Thảo Trần, Barbara A. Moreno Diaz, Sarah I. Patel, Fiorella Schischlik-Siegl
article en
4 citations

Abstract

<i>KRAS</i> 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 evaluated the preclinical efficacy of BI-2493, a first-in-class allele-agnostic mutant-KRAS inhibitor (panKRASi), in pancreatic ductal adenocarcinoma (PDAC). We report effective tumor growth suppression across a broad range of models, including cell lines, patient-derived xenografts (PDXs), and syngeneic orthotopic models, and prolonged survival in genetically engineered mouse models. Overall, transcriptomic, proteomic, and phosphoproteomic profiling of panKRASi-treated models confirmed RAS pathway inhibition along with up-regulation of LKB1/AMPK (liver kinase B1/AMP-activated protein kinase) targets. In panKRASi-treated immune-replete models, we observed increased intratumoral CD8<sup>+</sup> 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 in the TME that impede effective T cell function. Our multifaceted approach identified potential combinatorial approaches for generating sustained responses to panKRASi.

Science Translational MedicineVol. 17(814)
Broad Institute (US), University of North Carolina at Chapel Hill (US), Boehringer Ingelheim (Germany) (DE), The University of Texas MD Anderson Cancer Center (US), Baylor College of Medicine (US), Boehringer Ingelheim (Austria) (AT), The University of Texas Medical Branch at Galveston (US), Rice University (US)
Openalex Percentile: Top 7%
Phagocytosis and Immune Regulation
3.19
DOIOpen Access PDFOpenAlex
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