克拉斯
胰腺癌
癌症研究
体内
肿瘤微环境
癌症
癌基因
免疫系统
生物
药理学
医学
免疫学
肿瘤细胞
细胞周期
内科学
结直肠癌
生物技术
作者
Samantha B. Kemp,Noah Cheng,Nune Markosyan,Rina Sor,Il‐Kyu Kim,Jill Hallin,Jason Shoush,Liz Quinones,Natalie V. Brown,Jared B. Bassett,Nikhil Joshi,Salina Yuan,Molly Smith,William P. Vostrejs,Kia Z. Perez-Vale,Benjamin Kahn,Feiyan Mo,Timothy R. Donahue,Caius G. Radu,Cynthia Clendenin,James G. Christensen,Robert H. Vonderheide,Ben Z. Stanger
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2022-12-06
卷期号:13 (2): 298-311
被引量:111
标识
DOI:10.1158/2159-8290.cd-22-1066
摘要
Abstract Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14 days. Concomitant with tumor cell apoptosis and proliferative arrest, drug treatment led to marked shifts in the tumor microenvironment (TME), including changes in fibroblasts, matrix, and macrophages. T cells were necessary for MRTX1133's full antitumor effect, and T-cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KRASG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies. Significance: Pharmacologic inhibition of KRASG12D in pancreatic cancer models with an intact immune system stimulates specific, potent, and durable tumor regressions. In the absence of overt toxicity, these results suggest that this and similar inhibitors should be tested as potential, high-impact novel therapies for patients with PDAC. See related commentary by Redding and Grabocka, p. 260. This article is highlighted in the In This Issue feature, p. 247
科研通智能强力驱动
Strongly Powered by AbleSci AI