Yoshida Takeshi, Okamoto Isamu, Okabe Takafumi, Iwasa Tsutomu, Satoh Taroh, Nishio Kazuto, Fukuoka Masahiro, Nakagawa Kazuhiko
Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
Int J Cancer. 2008 Apr 1;122(7):1530-8. doi: 10.1002/ijc.23253.
Molecular inhibition of the epidermal growth factor receptor (EGFR) is a promising anticancer strategy, and monoclonal antibodies (mAbs) to EGFR are undergoing extensive evaluation in preclinical and clinical trials. However, the effects of anti-EGFR mAbs on EGFR signaling have remained unclear. We have now examined the effects of 2 anti-EGFR mAbs, matuzumab (EMD72000) and cetuximab (Erbitux), both of which are currently under assessment for treatment of various cancers, on EGFR signal transduction and cell survival in nonsmall cell lung cancer cell lines. Similar to EGF, matuzumab and cetuximab each induced phosphorylation of EGFR at several tyrosine phosphorylation sites as a result of receptor dimerization and activation of the receptor tyrosine kinase. In contrast to the effects of EGF, however, EGFR activation induced by these antibodies was not accompanied by receptor turnover or by activation of downstream signaling pathways that are mediated by Akt and Erk and are important for regulation of cell proliferation and survival. In addition, clonogenic survival assays revealed that matuzumab and cetuximab reduced the survival rate of H292 cells, in which they also inhibited the EGF-induced activation of Akt and Erk. Although we have examined only a few cell lines, our results indicate that the antitumor effects of matuzumab and cetuximab depend on inhibition of EGFR downstream signaling mediated by Akt or Erk rather than on inhibition of EGFR itself.
对表皮生长因子受体（EGFR）进行分子抑制是一种很有前景的抗癌策略，针对EGFR的单克隆抗体（mAb）正在临床前和临床试验中接受广泛评估。然而，抗EGFR mAb对EGFR信号传导的影响仍不清楚。我们现在研究了两种抗EGFR mAb，即美妥珠单抗（EMD72000）和西妥昔单抗（爱必妥）对非小细胞肺癌细胞系中EGFR信号转导和细胞存活的影响，这两种药物目前都在接受治疗各种癌症的评估。与表皮生长因子（EGF）相似，美妥珠单抗和西妥昔单抗各自通过受体二聚化和受体酪氨酸激酶的激活，诱导EGFR在多个酪氨酸磷酸化位点发生磷酸化。然而，与EGF的作用不同，这些抗体诱导的EGFR激活并未伴随受体更新，也未激活由Akt和Erk介导的对细胞增殖和存活调节很重要的下游信号通路。此外，克隆形成存活分析显示，美妥珠单抗和西妥昔单抗降低了H292细胞的存活率，它们在H292细胞中还抑制了EGF诱导的Akt和Erk激活。尽管我们只研究了少数细胞系，但我们的结果表明，美妥珠单抗和西妥昔单抗的抗肿瘤作用取决于对由Akt或Erk介导的EGFR下游信号传导的抑制，而不是对EGFR本身的抑制。
