通过伯马替尼（pemigatinib）针对FGFRs的作用，在细胞周期中导致G1期的细胞周期停滞，细胞应激以及肿瘤抑制因子miRNA的上调。
Targeting FGFRs by pemigatinib induces G1 phase cell cycle arrest, cellular stress and upregulation of tumor suppressor microRNAs.
发表日期：2023 Sep 15
作者：
Angelica Pace, Fabio Scirocchi, Chiara Napoletano, Ilaria Grazia Zizzari, Agnese Po, Francesca Megiorni, Angela Asquino, Paola Pontecorvi, Hassan Rahimi, Cinzia Marchese, Elisabetta Ferretti, Marianna Nuti, Aurelia Rughetti
来源：
Cellular & Molecular Immunology
摘要：
纤维母细胞生长因子受体(FGFR)基因家族的突变在几种癌症中被发现，表明它们作为潜在治疗靶点的重要性。FGFR-酪氨酸激酶抑制剂(pemigatinib)已被引入用于晚期胆管癌的治疗，最近还用于FGFR2和FGFR1重排的复发或难治性髓系/淋巴瘤样恶性肿瘤的治疗。目前有几项临床试验正在研究pemigatinib与免疫疗法的可能联合应用。在本研究中，我们分析了pemigatinib对不同癌细胞模型(肺、膀胱和胃)的生物学和分子效应，这些模型目前正是临床试验研究的对象。通过qRT-PCR和Western blot评估了NCI-H1581肺癌、KATO III胃癌和RT-112膀胱癌细胞系中FGFR的表达。细胞系经过Pem处理后，对细胞增殖、凋亡、细胞内产生的反应性氧自由基(ROS)的产生以及衰老的诱导进行了表征。通过qRT-PCR分析了具有抑制肿瘤功能的微小RNA的表达，通过Western blot和mRNA评估了它们靶基因编码的蛋白质的调控情况。描述性统计用于分析各种数据，学生t检验用于比较两组分析。Pemigatinib处理引发了不同的信号通路，并减少了所有癌细胞的增殖能力，诱导了G1期细胞周期停滞以及强烈的细胞内应激，导致ROS的产生、衰老和凋亡。Pemigatinib治疗还导致具有抑制肿瘤功能的微小RNA(miR-133b、miR-139、miR-186、miR-195)的上调，同时使具有致癌作用的已验证蛋白质靶点(c-Myc、c-MET、CDK6、EGFR)的表达下调。这些结果有助于阐明抗FGFR酪氨酸激酶抑制剂pemigatinib在不同肿瘤环境中介导的生物学效应和分子机制，并支持其用于联合治疗的开发利用。© 2023. BioMed Central Ltd., part of Springer Nature.
Fibroblast growth factor receptor (FGFR) gene family alterations are found in several cancers, indicating their importance as potential therapeutic targets. The FGFR-tyrosine kinase inhibitor (TKI) pemigatinib has been introduced in the treatment of advanced cholangiocarcinoma and more recently for relapsed or refractory myeloid/lymphoid neoplasms with FGFR2 and FGFR1 rearrangements, respectively. Several clinical trials are currently investigating the possible combination of pemigatinib with immunotherapy. In this study, we analyzed the biological and molecular effects of pemigatinib on different cancer cell models (lung, bladder, and gastric), which are currently objective of clinical trial investigations.NCI-H1581 lung, KATO III gastric and RT-112 bladder cancer cell lines were evaluated for FGFR expression by qRT-PCR and Western blot. Cell lines were treated with Pem and then characterized for cell proliferation, apoptosis, production of intracellular reactive oxygen species (ROS), and induction of senescence. The expression of microRNAs with tumor suppressor functions was analyzed by qRT-PCR, while modulation of the proteins coded by their target genes was evaluated by Western blot and mRNA. Descriptive statistics was used to analyze the various data and student's t test to compare the analysis of two groups.Pemigatinib exposure triggered distinct signaling pathways and reduced the proliferative ability of all cancer cells, inducing G1 phase cell cycle arrest and strong intracellular stress resulting in ROS production, senescence and apoptosis. Pemigatinib treatment also caused the upregulation of microRNAs (miR-133b, miR-139, miR-186, miR-195) with tumor suppressor functions, along with the downregulation of validated protein targets with oncogenic roles (c-Myc, c-MET, CDK6, EGFR).These results contribute to clarifying the biological effects and molecular mechanisms mediated by the anti-FGFR TKI pemigatinib in distinct tumor settings and support its exploitation for combined therapies.© 2023. BioMed Central Ltd., part of Springer Nature.