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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Quantitative analysis of EGFRvⅢ cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma
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Quantitative analysis of EGFRvⅢ cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma

机译：EGFRvⅢ细胞信号网络的定量分析揭示了胶质母细胞瘤的联合治疗策略

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Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults and remains incurable despite multimodal intensive treatment regimens. EGFRvⅢ is a truncated extracellular mutant of the EGF receptor (EGFR) commonly found in GBMs that confers enhanced tumorigenic behavior. To gain a molecular understanding of the mechanisms by which EGFRvⅢ acts, we have performed a large-scale analysis of EGFRvⅢ-activated phosphotyrosine-mediated signaling pathways and thereby have identified and quantified 99 phosphorylation sites on 69 proteins. Distinct signaling responses were observed as a function of titrated EGFRvⅢ receptor levels with the phosphatidylinositol 3-kinase pathway being dominant over the MAPK and STAT3 pathways at a high level of EGFRvⅢ expression. Within this data set, the activating phosphorylation site on the c-Met receptor was found to be highly responsive to EGFRvⅢ levels, indicating cross-activation of the c-Met receptor tyrosine kinase by EGFRvⅢ. To determine the significance of this finding, we devised a combined treatment regimen that used a c-Met kinase inhibitor and either an EGFR kinase inhibitor or cisplatin. This regimen resulted in enhanced cytotoxicity of EGFRvⅢ-expressing cells compared with treatment with either compound alone. These results suggest that the clinical use of c-Met kinase inhibitors in combination with either EGFR inhibitors or standard chemotherapeutics might represent a previously undescribed therapeutic approach to overcome the observed chemoresistance in patients with GBMs expressing EGFRvⅢ.
机译：多形胶质母细胞瘤（GBM）是成人中最具侵袭性的脑肿瘤，尽管采取了多模式强化治疗方案，但仍无法治愈。 EGFRvⅢ是EGF受体（EGFR）的一种截短的细胞外突变体，通常在GBM中发现，具有增强的致瘤性。为了对EGFRvⅢ的作用机理有一个分子的了解，我们对EGFRvⅢ激活的磷酸酪氨酸介导的信号通路进行了大规模分析，从而鉴定并定量了69个蛋白质上的99个磷酸化位点。观察到明显的信号响应是滴定的EGFRvⅢ受体水平的函数，在高水平的EGFRvⅢ表达下，磷脂酰肌醇3-激酶途径优于MAPK和STAT3途径。在此数据集中，发现c-Met受体上的活化磷酸化位点对EGFRvⅢ水平高度敏感，表明EGFRvⅢ对c-Met受体酪氨酸激酶有交叉激活作用。为了确定这一发现的重要性，我们设计了一种联合治疗方案，该方案使用c-Met激酶抑制剂和EGFR激酶抑制剂或顺铂。与单独使用任一化合物处理相比，该方案可提高表达EGFRvⅢ的细胞的细胞毒性。这些结果表明，将c-Met激酶抑制剂与EGFR抑制剂或标准化学疗法联合使用可能代表了一种先前未描述的治疗方法，可以克服表达EGFRvⅢ的GBM患者所观察到的化学耐药性。

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