胰腺癌患者对致癌 KRAS 抑制剂产生耐药性的机制。

IF 29.7 1区 医学 Q1 ONCOLOGY Cancer discovery Pub Date : 2024-11-01 DOI:10.1158/2159-8290.CD-24-0177
Julien Dilly, Megan T Hoffman, Laleh Abbassi, Ziyue Li, Francesca Paradiso, Brendan D Parent, Connor J Hennessey, Alexander C Jordan, Micaela Morgado, Shatavisha Dasgupta, Giselle A Uribe, Annan Yang, Kevin S Kapner, Felix P Hambitzer, Li Qiang, Hanrong Feng, Jacob Geisberg, Junning Wang, Kyle E Evans, Hengyu Lyu, Aislyn Schalck, Ningping Feng, Anastasia M Lopez, Christopher A Bristow, Michael P Kim, Kimal I Rajapakshe, Vahid Bahrambeigi, Jennifer A Roth, Kavita Garg, Paola A Guerrero, Ben Z Stanger, Simona Cristea, Scott W Lowe, Timour Baslan, Eliezer M Van Allen, Joseph D Mancias, Emily Chan, Abraham Anderson, Yuliya V Katlinskaya, Alex K Shalek, David S Hong, Shubham Pant, Jill Hallin, Kenna Anderes, Peter Olson, Timothy P Heffernan, Seema Chugh, James G Christensen, Anirban Maitra, Brian M Wolpin, Srivatsan Raghavan, Jonathan A Nowak, Peter S Winter, Stephanie K Dougan, Andrew J Aguirre
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引用次数: 0

摘要

KRAS抑制剂对胰腺导管腺癌(PDAC)具有临床疗效,但耐药性也很常见。在接受阿达拉西布或索托拉西布治疗的KRASG12C突变PDAC患者中,PIK3CA和KRAS突变以及KRASG12C、MYC、MET、表皮生长因子受体和CDK6扩增出现了获得性耐药。在用KRASG12D抑制剂MRTX1133治疗的PDAC细胞系和类器官模型中,上皮细胞向间质转化和PI3K-AKT-mTOR信号转导与耐药性有关。MRTX1133治疗KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre(KPC)小鼠模型可使肿瘤深度消退,但最终会出现耐药性,同时伴有Kras、Yap1、Myc和Cdk6/Abcb1a/b的扩增以及耐药性转录程序的共同进化。此外,在 KPC 和 PDX 模型中,间质细胞和基底样细胞状态对 KRAS 抑制的反应比经典状态更强。在 PDAC 小鼠模型中,KRASG12D 抑制与化疗的联合治疗能显著提高肿瘤控制率。总之,这些数据阐明了 KRAS 抑制的共同耐药机制,并支持多种联合治疗策略。
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Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer.

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+; Trp53LSL-R172H/+; p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, Cdk6, and Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies. Significance: Acquired resistance may limit the impact of KRAS inhibition in patients with PDAC. Using clinical samples and multiple preclinical models, we define heterogeneous genetic and non-genetic mechanisms of resistance to KRAS inhibition that may guide combination therapy approaches to improve the efficacy and durability of these promising therapies for patients. See related commentary by Marasco and Misale, p. 2018.

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来源期刊
Cancer discovery
Cancer discovery ONCOLOGY-
CiteScore
22.90
自引率
1.40%
发文量
838
审稿时长
6-12 weeks
期刊介绍: Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.
期刊最新文献
Clinical Validation of a Cell-Free DNA Fragmentome Assay for Augmentation of Lung Cancer Early Detection. The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma. Single-Cell View of Tumor Microenvironment Gradients in Pleural Mesothelioma. A Classical Epithelial State Drives Acute Resistance to KRAS Inhibition in Pancreatic Cancer. Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer.
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