Zimmer Sebastian, Kahl Philip, Buhl Theresa M, Steiner Susanne, Wardelmann Eva, Merkelbach-Bruse Sabine, Buettner Reinhard, Heukamp Lukas C
Institute of Pathology, University Hospital Bonn, Sigmund-Freud-Strasse 25, Bonn, Germany.
J Cancer Res Clin Oncol. 2009 May;135(5):723-30. doi: 10.1007/s00432-008-0509-9. Epub 2008 Nov 11.
The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) has been linked to activating mutations in the EGFR gene. So far these mutations have been extensively characterized in established cell lines. The aim of this study was to determine the effects of EGFR mutations on downstream signaling in human tumor specimens.
We have looked for mutations of the EGFR gene in specimens of 67 patients with NSCLC and correlated these with EGFR phosphorylation and the activity of its three main downstream signaling cascades Akt, MAPK and Stat3 by immunohistochemistry.
We show that the phosphorylation of tyrosine residues 922 and 1173, but not 1068, are primarily affected by the activating EGFR mutations. Akt activity was significantly higher in patients with EGFR mutations but we found no difference in Stat3 or MAPK phosphorylation. Our results suggest that EGFR mutations not only increase receptor activity, but also alter responses of downstream signaling cascades in human NSCLCs and that these finding differ from results obtained in cell lines.
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂在非小细胞肺癌（NSCLC）中的疗效与EGFR基因的激活突变有关。到目前为止，这些突变已在已建立的细胞系中得到广泛表征。本研究的目的是确定EGFR突变对人肿瘤标本中下游信号传导的影响。
我们在67例NSCLC患者的标本中寻找EGFR基因的突变，并通过免疫组织化学将这些突变与EGFR磷酸化及其三个主要下游信号级联反应Akt、MAPK和Stat3的活性相关联。
我们表明，酪氨酸残基922和1173的磷酸化，而非1068的磷酸化，主要受激活的EGFR突变影响。EGFR突变患者的Akt活性显著更高，但我们发现Stat3或MAPK磷酸化没有差异。我们的结果表明，EGFR突变不仅增加受体活性，还改变人NSCLC中下游信号级联反应的反应，并且这些发现与在细胞系中获得的结果不同。
