一种等位基因不可知的突变型kras抑制剂抑制肿瘤维持信号并重新编程胰腺癌的肿瘤免疫

IF 14.6 1区 医学 Q1 CELL BIOLOGY
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
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引用次数: 0

摘要

KRAS是癌症中最常见的突变癌基因之一,几十年来,在实体癌中药物阻断其功能的努力一直没有成功。这方面的一个显著进展是最近开发的小分子KRAS抑制剂,它可以直接靶向突变的癌蛋白。在这里,我们全面评估了BI-2493在胰腺导管腺癌(PDAC)中的临床前疗效,BI-2493是一种同类中第一种等位基因不可知性突变型kras抑制剂(panKRASi)。我们报道了在广泛的模型中有效的肿瘤生长抑制,包括细胞系、患者来源的异种移植物(PDXs)和同基因原位模型,并延长了基因工程小鼠模型的存活时间。总的来说,pankrasi处理模型的转录组学、蛋白质组学和磷酸化蛋白质组学分析证实了RAS通路的抑制以及LKB1/AMPK(肝激酶B1/ amp活化蛋白激酶)靶点的上调。在pankrasi治疗的免疫充满模型中,我们观察到肿瘤内CD8+效应T细胞增加,骨髓细胞浸润减少,以及肿瘤微环境(TME)的重塑,使免疫检查点封锁产生反应。从长期来看,对panKRASi单药治疗的耐药性的出现与肿瘤细胞内YAP信号的增加和TME中阻碍有效T细胞功能的免疫检查点的表达增强有关。我们的多方面方法确定了潜在的组合方法,以产生对panKRASi的持续反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer
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.
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
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. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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