Signaling networks assembled by oncogenic EGFR and c-Met
Signaling networks assembled by oncogenic EGFR and c-Met
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DOI：
10.1073/pnas.0707270105
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发表时间：
2008-01-15
影响因子：
11.1
通讯作者：
Comb, Michael J.
中科院分区：
文献类型：
--
作者：
Guo, Ailan;Villen, Judit;Comb, Michael J.
关于实体瘤对靶向激酶抑制剂的敏感性的一个主要问题是为什么一些肿瘤有反应而另一些没有。许多肿瘤表达表皮生长因子受体（EGFR），但只有一小部分EGFR激活突变的肿瘤对EGFR抑制剂（EGFR抑制剂）有临床反应，这表明有反应的肿瘤的生存唯一依赖于EGFR信号传导。这种依赖性的本质还不清楚。在这里，我们调查依赖EGFR信号通过比较非小细胞肺癌细胞系驱动EGFR激活突变和基因组扩增使用磷酸酪氨酸信号的全球蛋白质组学分析。我们确定了一个广泛的受体酪氨酸激酶信号网络建立在细胞表达突变和激活的EGFR或表达扩增的c-Met。我们发现，在药物敏感细胞中，靶向酪氨酸激酶驱动其他RTK和广泛的下游信号网络，这些网络随着药物治疗而崩溃。EGFR和c-Met依赖性细胞中信号网络的比较鉴定了参与介导药物反应的途径的约50种蛋白质的“核心网络”。
A major question regarding the sensitivity of solid tumors to targeted kinase inhibitors is why some tumors respond and others do not. The observation that many tumors express EGF receptor (EGFR), yet only a small subset with EGFR-activating mutations respond clinically to EGFR inhibitors (EGFRIs), suggests that responsive tumors uniquely depend on EGFR signaling for their survival. The nature of this dependence is not understood. Here, we investigate dependence on EGFR signaling by comparing non-small-cell lung cancer cell lines driven by EGFR-activating mutations and genomic amplifications using a global proteomic analysis of phospho-tyrosine signaling. We identify an extensive receptor tyrosine kinase signaling network established in cells expressing mutated and activated EGFR or expressing amplified c-Met. We show that in drug sensitive cells the targeted tyrosine kinase drives other RTKs and an extensive network of downstream signaling that collapse with drug treatment. Comparison of the signaling networks in EGFR and c-Met-dependent cells identify a "core network" of approximate to 50 proteins that participate in pathways mediating drug response.