NR2F1升高是braf突变黑色素瘤治疗后侵袭性疾病持续存在的基础。

IF 13.6 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Journal of Clinical Investigation Pub Date : 2025-07-29 eCollection Date: 2025-09-16 DOI:10.1172/JCI178446
Manoela Tiago, Timothy J Purwin, Casey D Stefanski, Renaira Oliveira da Silva, Mitchell E Fane, Yash Chhabra, Jelan I Haj, Jessica Lf Teh, Rama Kadamb, Weijia Cai, Sheera R Rosenbaum, Vivian Chua, Nir Hacohen, Michael A Davies, Jessie Villanueva, Inna Chervoneva, Ashani T Weeraratna, Dan A Erkes, Claudia Capparelli, Julio A Aguirre-Ghiso, Andrew E Aplin
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引用次数: 0

摘要

尽管靶向抑制剂在皮肤黑色素瘤中取得了成功,但治疗反应受到肿瘤微环境老化和耐药残留细胞的限制。鉴于药物耐受性与细胞休眠之间的相似性,我们研究了休眠标志物核受体亚家族2组F成员1 (NR2F1)对BRAF-V600E抑制剂(BRAFi)和MEK抑制剂(MEKi)在braf突变黑色素瘤模型中的反应。用BRAFi + MEKi治疗的黑色素瘤患者样本的转录组学分析显示NR2F1增加。NR2F1在BRAFi + MEKi上患者源性和小鼠源性异种移植物的最小残留病的耐药侵袭细胞状态下高度表达。NR2F1过表达足以降低BRAFi + MEKi对体内肿瘤生长和体外细胞增殖、死亡和侵袭的影响。这些影响与mTORC1信号传导相关的基因有关。这些细胞对BRAFi、MEKi和雷帕霉素的联合作用敏感。来自老年小鼠的黑色素瘤,已知对BRAFi + MEKi的反应降低,与来自年轻小鼠的肿瘤相比,显示出更高水平的NR2F1。在老年小鼠黑色素瘤中消耗NR2F1改善了对靶向治疗的反应。这些发现表明NR2F1在“侵袭状态”残余细胞中高表达,并且用mTORC1抑制剂靶向NR2F1高表达的细胞可能改善黑色素瘤患者的预后。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Elevated NR2F1 underlies the persistence of invasive disease after treatment of BRAF-mutant melanoma.

Despite the success of targeted inhibitors in cutaneous melanoma, therapeutic responses are limited by the aged tumor microenvironment and drug-tolerant residual cells. Given the similarities between drug tolerance and cellular dormancy, we studied the dormancy marker, nuclear receptor subfamily 2 group F member 1 (NR2F1), in response to BRAF-V600E inhibitors (BRAFi) plus MEK inhibitors (MEKi) in BRAF-mutant melanoma models. Transcriptomic analysis of melanoma patient samples treated with BRAFi + MEKi showed increased NR2F1. NR2F1 was highly expressed in the drug-tolerant invasive cell state of minimal residual disease in patient-derived and mouse-derived xenografts on BRAFi + MEKi. NR2F1 over-expression was sufficient to reduce BRAFi + MEKi effects on tumor growth in vivo, and cell proliferation, death, and invasion in vitro. Effects were linked to genes involved in mTORC1 signaling. These cells were sensitive to the combination of BRAFi, MEKi plus rapamycin. Melanomas from aged mice, known to exhibit decreased responses to BRAFi + MEKi, displayed higher levels of NR2F1 compared to tumors from young mice. Depleting NR2F1 in an aged mouse melanomas improved the response to targeted therapy. These findings show high NR2F1 expression in 'invasive-state' residual cells and that targeting NR2F1-high cells with mTORC1 inhibitors may improve outcomes in patients with melanoma.

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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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