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Quantitative proteomics analysis identifies MUC1 as an effect sensor of EGFR inhibition.
Oncogene ( IF 6.9 ) Pub Date : 2018-Oct-10 , DOI: 10.1038/s41388-018-0522-7
H. Rudolf de Boer , Martin Pool , Esméé Joosten , Marieke Everts , Douwe F. Samplonius , Wijnand Helfrich , Harry J. M. Groen , Suzanne van Cooten , Fabrizia Fusetti , Rudolf S. N. Fehrmann , Elisabeth G. E. de Vries , Marcel A. T. M. van Vugt

Tumor responses to cancer therapeutics are generally monitored every 2-3 months based on changes in tumor size. Dynamic biomarkers that reflect effective engagement of targeted therapeutics to the targeted pathway, so-called "effect sensors", would fulfill a need for non-invasive, drug-specific indicators of early treatment effect. Using a proteomics approach to identify effect sensors, we demonstrated MUC1 upregulation in response to epidermal growth factor receptor (EGFR)-targeting treatments in breast and lung cancer models. To achieve this, using semi-quantitative mass spectrometry, we found MUC1 to be significantly and durably upregulated in response to erlotinib, an EGFR-targeting treatment. MUC1 upregulation was regulated transcriptionally, involving PI3K-signaling and STAT3. We validated these results in erlotinib-sensitive human breast and non-small lung cancer cell lines. Importantly, erlotinib treatment of mice bearing SUM149 xenografts resulted in increased MUC1 shedding into plasma. Analysis of MUC1 using serial blood sampling may therefore be a new, relatively non-invasive tool to monitor early and drug-specific effects of EGFR-targeting therapeutics.

中文翻译:

定量蛋白质组学分析确定MUC1是EGFR抑制作用的传感器。

通常基于肿瘤大小的变化,每2-3个月监测一次对癌症治疗剂的肿瘤反应。反映靶向治疗剂对靶向途径有效参与的动态生物标记物,即所谓的“效应传感器”,将满足对早期治疗效果的非侵入性,药物特异性指示剂的需求。使用蛋白质组学方法识别效应传感器,我们在乳腺癌和肺癌模型中证明了针对表皮生长因子受体(EGFR)靶向治疗的MUC1上调。为了实现这一目标,我们使用半定量质谱分析法发现,针对EGFR靶向治疗埃洛替尼,MUC1被显着持久地上调。MUC1上调是转录调控,涉及PI3K信号和STAT3。我们在对厄洛替尼敏感的人乳腺癌和非小细胞肺癌细胞系中验证了这些结果。重要的是,厄洛替尼对带有SUM149异种移植物的小鼠的治疗导致MUC1释放入血浆的增加。因此,使用连续血样分析MUC1可能是一种新的,相对非侵入性的工具,可以监测靶​​向EGFR的治疗药物的早期和药物特异性作用。
更新日期:2018-10-11
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