title: Lapatinib inhibits receptor phosphorylation and cell growth and enhances antibody-dependent cellular cytotoxicity of EGFR- and HER2-overexpressing esophageal cancer cell lines.
abstract: Lapatinib is a dual tyrosine kinase inhibitor of the EGFR and HER2 tyrosine kinase domains. EGFR is expressed in 33.3% and HER2 in 30.3% of esophageal squamous cell carcinomas (ESCCs). To explore the potential utility of Lapatinib for therapy of ESCC patients, we evaluated the effect of Lapatinib on a panel of ESCC cell lines. EGFR and HER2 expression by the cell lines was established, and the effects of Lapatinib on inhibition of the phosphorylation of HER2, antiproliferative effect, apoptosis-inducing activity and accumulation of HER2 and EGFR on cell surface were evaluated. Additionally, the combined effect of Lapatinib together with Herceptin or Cetuximab on cell-mediated cytotoxicity was evaluated. Lapatinib inhibited HER2 phosphorylation in HER2-overexpressing, HER2 gene amplification positive ESCC cell line. Lapatinib also inhibited cell proliferation, induced apoptosis and caused the surface accumulation of HER2 and EGFR in ESCC cell lines. Addition of Lapatinib increased Herceptin-mediated antibody-dependent cell-mediated cytotoxicity by 15-25% with three ESCC target cell lines. Similarly, Cetuximab-mediated antibody-dependent cell-mediated cytotoxicity also increased by 15-30% in two ESCC cell lines on addition of Lapatinib. Cumulatively, the data indicate that Lapatinib has activity in EGFR- and/or HER2-expressing ESCC cells, and the combination therapy of Lapatinib and Cetuximab/Herceptin is a promising strategy in ESCC.
authors.affiliation: First Department of Surgery, University of Yamanashi, Yamanashi, Japan.
authors.forename: Kousaku
authors.initials: K
authors.lastname: Mimura
authors.forename: Koji
authors.initials: K
authors.lastname: Kono
authors.forename: Takanori
authors.initials: T
authors.lastname: Maruyama
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Izawa
authors.forename: Shugo
authors.initials: S
authors.lastname: Shiba
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Mizukami
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kono
authors.forename: Aniruddha
authors.initials: A
authors.lastname: Choudhury
authors.forename: Rolf
authors.initials: R
authors.lastname: Kiessling
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000235:genetics*; D018734:Genes, erbB-2; D006801:Humans; D000077341:Lapatinib; D018307:Neoplasms, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077341:Lapatinib; D066246:ErbB Receptors