Pertuzumab, a novel HER dimerization inhibitor, inhibits the growth of human lung cancer cells mediated by the HER3 signaling pathway
Pertuzumab, a novel HER dimerization inhibitor, inhibits the growth of human lung cancer cells mediated by the HER3 signaling pathway
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DOI：
10.1111/j.1349-7006.2007.00553.x
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发表时间：
2007-09-01
期刊：
影响因子：
5.7
通讯作者：
Nishio, Kazuto
中科院分区：
文献类型：
--
作者：
Sakai, Kazuko;Yokote, Hideyuki;Nishio, Kazuto
一种人源化抗HER2单克隆抗体pertuzumab （Omnitarg, 2C4）与曲妥珠单抗结合不同的HER2表位，被认为是HER受体异源二聚化的抑制剂。对表达her2的乳腺癌和前列腺癌细胞系的有效抗肿瘤活性已被证实，但对肺癌的潜在抗肿瘤活性尚不清楚。作者研究了帕妥珠单抗对8种表达HER受体不同成员的非小细胞肺癌细胞的体外抗肿瘤活性。肺癌11_18细胞系大量表达HER2和HER3，其细胞生长受到HER3配体heregulin (HRG)- α的刺激。Pertuzumab显著抑制hrg - α刺激的11_18细胞的生长。Pertuzumab阻断hrg - α刺激的HER3、丝裂原活化蛋白激酶（MAPK）和Akt的磷酸化。相比之下，帕妥珠单抗未能阻断表皮生长因子（EGF）刺激的EGF受体（EGFR）和MAPK的磷酸化。免疫沉淀显示，帕妥珠单抗抑制hrg - α刺激的HER2/HER3异源二聚体的形成。在共同过表达EGFR、HER2和HER3的PC-9细胞中也观察到hrg - α刺激的HER3磷酸化，但hrg - α既不刺激细胞生长，也不抑制帕妥珠单抗。目前的结果表明，帕妥珠单抗通过抑制hrg - α刺激的HER2/HER3信号传导，有效抑制肺癌细胞中hrg - α依赖的细胞生长。
A humanized anti-HER2 monoclonal antibody pertuzumab (Omnitarg, 2C4), binding to a different HER2 epitope than trastuzumab, is known as an inhibitor of heterodimerization of the HER receptors. Potent antitumor activity against HER2-expressing breast and prostate cancer cell lines has been clarified, but this potential is not clear against lung cancers. The authors investigated the in vitro anti-tumor activity of pertuzumab against eight non-small cell lung cancer cells expressing various members of the HER receptors. A lung cancer 11_18 cell line expressed a large amount of HER2 and HER3, and its cell growth was stimulated by an HER3 ligand, heregulin (HRG)-alpha. Pertuzumab significantly inhibited the HRG-alpha-stimulated cellular growth of the 11_18 cells. Pertuzumab blocked HRG-alpha-stimulated phosphorylation of HER3, mitogen-activated protein kinase (MAPK), and Akt. In contrast, pertuzumab failed to block epidermal growth factor (EGF)-stimulated phosphorylation of EGF receptor (EGFR) and MAPK. Immunoprecipitation showed that pertuzumab inhibited HRG-alpha-stimulated HER2/HER3 heterodimer formation. HRG-alpha-stimulated HER3 phosphorylation was also observed in the PC-9 cells co-overexpressing EGFR, HER2, and HER3, but the cell growth was neither stimulated by HRG-alpha nor inhibited by pertuzumab. The present results suggest that pertuzumab is effective against HRG-alpha-dependent cell growth in lung cancer cells through inhibition of HRG-alpha-stimulated HER2/HER3 signaling.