Chien-Yun Lee, Matthew The, Chen Meng, Florian P Bayer, Kerstin Putzker, Julian Müller, Johanna Streubel, Julia Woortman, Amirhossein Sakhteman, Moritz Resch, Annika Schneider, Stephanie Wilhelm, Bernhard Kuster
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引用次数: 0
摘要
激酶抑制剂(KIs)是重要的抗癌药物,但往往具有分子上不为人知的多药理作用。这种脱节在肉瘤等癌症实体中尤为明显,因为肉瘤的致癌驱动因素往往并不明确。为了更系统地研究肉瘤细胞的细胞蛋白型如何影响它们对分子靶向药物的反应,我们分析了 17 种肉瘤细胞系的蛋白质组和磷酸蛋白组,并针对 150 种抗癌药物进行了筛选。由此产生的 2550 个表型图谱揭示了不同的药物反应,而从深度(磷酸)蛋白质组(每个细胞系有 9-10,000 个蛋白质和 10-27,000 个磷酸化位点)中得出的细胞活性图谱促成了多种分析方法。例如,将(磷酸化)蛋白质组数据与药物反应联系起来,可以揭示 KIs 的已知和新型作用机制 (MoAs),并确定药物敏感性或耐药性的标记。所有数据都可通过一个交互式网络应用程序公开访问,通过该程序可以探索这一丰富的分子资源,从而更好地了解肉瘤细胞中的活性信号通路,确定治疗反应预测因子,并揭示临床 KIs 的新作用机制。
Illuminating phenotypic drug responses of sarcoma cells to kinase inhibitors by phosphoproteomics.
Kinase inhibitors (KIs) are important cancer drugs but often feature polypharmacology that is molecularly not understood. This disconnect is particularly apparent in cancer entities such as sarcomas for which the oncogenic drivers are often not clear. To investigate more systematically how the cellular proteotypes of sarcoma cells shape their response to molecularly targeted drugs, we profiled the proteomes and phosphoproteomes of 17 sarcoma cell lines and screened the same against 150 cancer drugs. The resulting 2550 phenotypic profiles revealed distinct drug responses and the cellular activity landscapes derived from deep (phospho)proteomes (9-10,000 proteins and 10-27,000 phosphorylation sites per cell line) enabled several lines of analysis. For instance, connecting the (phospho)proteomic data with drug responses revealed known and novel mechanisms of action (MoAs) of KIs and identified markers of drug sensitivity or resistance. All data is publicly accessible via an interactive web application that enables exploration of this rich molecular resource for a better understanding of active signalling pathways in sarcoma cells, identifying treatment response predictors and revealing novel MoA of clinical KIs.
期刊介绍:
Systems biology is a field that aims to understand complex biological systems by studying their components and how they interact. It is an integrative discipline that seeks to explain the properties and behavior of these systems.
Molecular Systems Biology is a scholarly journal that publishes top-notch research in the areas of systems biology, synthetic biology, and systems medicine. It is an open access journal, meaning that its content is freely available to readers, and it is peer-reviewed to ensure the quality of the published work.