Huang Paul H, Mukasa Akitake, Bonavia Rudy, Flynn Ryan A, Brewer Zachary E, Cavenee Webster K, Furnari Frank B, White Forest M
Department of Biological Engineering and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12867-72. doi: 10.1073/pnas.0705158104. Epub 2007 Jul 23.
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.
多形性胶质母细胞瘤（GBM）是成人中最具侵袭性的脑肿瘤，尽管采用了多模式强化治疗方案，仍然无法治愈。表皮生长因子受体变异体Ⅲ型（EGFRvIII）是表皮生长因子受体（EGFR）的一种截短的细胞外突变体，常见于GBM中，具有增强的致瘤行为。为了从分子层面理解EGFRvIII发挥作用的机制，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种蛋白质上的99个磷酸化位点。随着EGFRvIII受体水平的滴定，观察到不同的信号反应，在EGFRvIII高表达水平时，磷脂酰肌醇3激酶途径比丝裂原活化蛋白激酶（MAPK）和信号转导子和转录激活子3（STAT3）途径占主导地位。在这个数据集中，发现c-Met受体上的激活磷酸化位点对EGFRvIII水平高度敏感，表明EGFRvIII对c-Met受体酪氨酸激酶具有交叉激活作用。为了确定这一发现的意义，我们设计了一种联合治疗方案，使用c-Met激酶抑制剂与EGFR激酶抑制剂或顺铂联合使用。与单独使用任何一种化合物相比，该方案导致表达EGFRvIII的细胞的细胞毒性增强。这些结果表明，c-Met激酶抑制剂与EGFR抑制剂或标准化疗药物联合临床使用，可能代表了一种以前未描述的治疗方法，以克服在表达EGFRvIII的GBM患者中观察到的化疗耐药性。
