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Pertuzumab (Omnitarg, 2C4), a humanized anti-HER2 monoclonal antibody binding to a different HER2 epitope than Herceptin is an inhibitor of heterodimerization of the HER family, and shows potent antitumor activity against HER2-expressing breast and prostate cancer cell lines. In lung cancer cells the EGFR plays a crucial role in their biological behavior, but it is unclear whether pertuzumab inhibits the growth of the lung cancer cells mediated by ErbB. In this study, we focused on the antiproliferative effect of pertuzumab on non-small cell lung cancer (NSCLC) cells expressing different types of ErbB receptors in vitro, and we analyzed the mechanism of action of pertuzumab in the response to ligand-mediated ErbB receptor activation. The lung cancer 11_18 cell line overexpresses HER2 and HER3 but not EGFR, and its cell growth was stimulated by a HER3 ligand heregulin. Pertuzumab significantly inhibited the heregulin-stimulated cellular growth of the 11_18 cells. Heregulin-induced phosphorylation of HER3, MAPK, and Akt was inhibited in a dose-dependent manner by exposure of the 11_18 cells to pertuzumab. Heregulin-stimulated HER3 phosphorylation was also observed in the PC-9 and Ma-1 cell lines that overexpress HER3 and EGFR but their cell growth was neither stimulated by heregulin nor inhibited by pertuzumab. These results suggest that the cellular growth of lung cancer cells overexpressing HER3 but not EGFR is highly heregulin-dependent, and that these cells are sensitive to pertuzumab.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]