Growth stimulation of non-small cell lung cancer cell lines by antibody against epidermal growth factor receptor promoting formation of ErbB2/ErbB3 heterodimers
Growth stimulation of non-small cell lung cancer cell lines by antibody against epidermal growth factor receptor promoting formation of ErbB2/ErbB3 heterodimers
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DOI：
10.1158/1541-7786.mcr-06-0303
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发表时间：
2007-04-01
影响因子：
5.2
通讯作者：
Ito, Fumiaki
中科院分区：
文献类型：
--
作者：
Maegawa, Mari;Takeuchi, Kenji;Ito, Fumiaki
抗体是人类治疗中发展最快的一类，包括它们在癌症治疗中的应用。针对表皮生长因子（EGF）受体（EGFR）的单克隆抗体（mAb）用于癌症治疗，可阻断配体与各种表达EGFR的人癌细胞系的结合，并消除配体依赖性细胞增殖。在这项研究中，我们表明，我们的单克隆抗体对EGFR，指定为B4 G7，表现出对各种人类癌细胞系，包括PC-14，非小细胞肺癌细胞系的生长刺激作用，虽然EGF对这些细胞系没有生长刺激活性。B4 G7单抗处理PC-14细胞后，EGFR发生酪氨酸磷酸化，并被EGFR酪氨酸激酶特异性抑制剂AG 1478完全抑制。然而，该抑制剂不影响B4 G7刺激的细胞生长，表明B4 G7 mAb的生长刺激似乎不依赖于EGFR酪氨酸激酶的活化。与抗ErbB 3抗体的免疫沉淀显示，B4 G7，而不是EGF，刺激ErbB 2和ErbB 3之间的异源二聚化。ErbB 3在B4 G7存在下酪氨酸磷酸化，但在EGF存在下不磷酸化。此外，ErbB 2的特异性抑制剂AG 825抑制了磷酸化和B4 G7诱导的细胞生长增加。这些结果表明，ErbB 2/ErbB 3二聚体在B4 G7处理的细胞中起到促进细胞生长的作用。抑制ErbB家族成员之一后，ErbB家族成员之间受体-受体相互作用的变化在优化目前EGFR家族定向的癌症治疗中具有潜在的重要性。
Antibodies are the most rapidly expanding class of human therapeutics, including their use in cancer therapy. Monoclonal antibodies (mAb) against epidermal growth factor (EGF) receptor (EGFR) generated for cancer therapy block the binding of ligand to various EGFR-expressing human cancer cell lines and abolish ligand-dependent cell proliferation. In this study, we show that our mAb against EGFRs, designated as B4G7, exhibited a growth-stimulatory effect on various human cancer cell lines including PC-14, a non-small cell lung cancer cell line; although EGF exerted no growth-stimulatory activity toward these cell lines. Tyrosine phosphorylation of EGFRs occurred after treatment of PC-14 cells with B4G7 mAb, and it was completely inhibited by AG1478, a specific inhibitor of EGFR tyrosine kinase. However, this inhibitor did not affect the B4G7-stimulated cell growth, indicating that the growth stimulation by B4G7 mAb seems to be independent of the activation of EGFR tyrosine kinase. Immunoprecipitation with anti-ErbB3 antibody revealed that B4G7, but not EGF, stimulated heterodimerization between ErbB2 and ErbB3. ErbB3 was tyrosine phosphorylated in the presence of B4G7 but not in the presence of EGF. Further, the phosphorylation and B4G7-induced increase in cell growth were inhibited by AG825, a specific inhibitor of ErbB2. These results show that the ErbB2/ErbB3 dimer functions to promote cell growth in B4G7-treated cells. Changes in receptor-receptor interactions between ErbB family members after inhibition of one of its members are of potential importance in optimizing current EGFR family-directed therapies for cancer.