Kathleen M. McAndrews, Francesca Paradiso, Clint A. Stalnecker, Benson S. Chellakkan, Fredrik I. Thege, David H. Peng, Barbara A. Moreno Diaz, Hikaru Sugimoto, Sarah I. Patel, Krishnan K. Mahadevan, Michelle L. Kirtley, Danielle Wills, Amari M. Sockwell, Andre Luis F. Fonseca, Yunhe Liu, Kimal I. Rajapakshe, Nathaniel G. Yee, Phuong Thao Tran, Huda Alchikh Omar, Antonio Tedeschi, Fiorella Schischlik-Siegl, Andrew S. Boghossian, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Dorothea Rudolph, Martin Aichinger, Florian Ebner, Artem V. Artemov, Jesse Lipp, Laura Pisarsky, Valerie Laura Herrmann, John Park, Jörg F. Rippmann, Otmar Schaaf, Vanessa Chandler, Mariah Williams, Charles E. Deckard, Linghua Wang, Channing J. Der, Christopher Vellano, Paola A. Guerrero, Timothy P. Heffernan, Raghu Kalluri, Anirban Maitra
{"title":"An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer","authors":"Kathleen M. McAndrews, Francesca Paradiso, Clint A. Stalnecker, Benson S. Chellakkan, Fredrik I. Thege, David H. Peng, Barbara A. Moreno Diaz, Hikaru Sugimoto, Sarah I. Patel, Krishnan K. Mahadevan, Michelle L. Kirtley, Danielle Wills, Amari M. Sockwell, Andre Luis F. Fonseca, Yunhe Liu, Kimal I. Rajapakshe, Nathaniel G. Yee, Phuong Thao Tran, Huda Alchikh Omar, Antonio Tedeschi, Fiorella Schischlik-Siegl, Andrew S. Boghossian, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Dorothea Rudolph, Martin Aichinger, Florian Ebner, Artem V. Artemov, Jesse Lipp, Laura Pisarsky, Valerie Laura Herrmann, John Park, Jörg F. Rippmann, Otmar Schaaf, Vanessa Chandler, Mariah Williams, Charles E. Deckard, Linghua Wang, Channing J. Der, Christopher Vellano, Paola A. Guerrero, Timothy P. Heffernan, Raghu Kalluri, Anirban Maitra","doi":"10.1126/scitranslmed.adt5511","DOIUrl":null,"url":null,"abstract":"<div ><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.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 814","pages":""},"PeriodicalIF":14.6000,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/scitranslmed.adt5511","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
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 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+ 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.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
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