title: Lapatinib acts on gastric cancer through both antiproliferative function and augmentation of trastuzumab-mediated antibody-dependent cellular cytotoxicity.
abstract: BACKGROUND
  Trastuzumab has been recently approved for clinical use to treat HER2-expressing advanced gastric cancer, and anti-HER2-targeting therapy has become a promising option for gastric cancer. Lapatinib is a dual tyrosine kinase inhibitor targeting EGFR and HER2. The aim of the present study was to explore the utility of lapatinib for gastric cancer, with a particular focus on trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC).
  
  
  METHODS
  Nine gastric cancer cell lines were evaluated for the effects of lapatinib on the cell-surface accumulation of HER2 and analyzed for their additional effects on trastuzumab-mediated ADCC. Also, HER2 signaling with Western blot, proliferative function with the MTT assay, and apoptosis-inducing activity with 7ADD/Annexin-V were investigated when a panel of gastric cancer cell lines was treated with lapatinib.
  
  
  RESULTS
  Lapatinib inhibited HER2 signaling and cell proliferation in the panel of gastric cancer cell lines. Lapatinib also induced the accumulation of HER2 on the cell surface, resulting in the enhancement of trastuzumab-mediated ADCC of gastric cancer.
  
  
  CONCLUSIONS
  Lapatinib exhibits inhibitory activity in gastric cancer cells, and the combination of lapatinib with trastuzumab may be a promising treatment strategy for gastric cancer patients.
authors.affiliation: First Department of Surgery, University of Yamanashi, Yamanashi, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Shiraishi
authors.forename: Kousaku
authors.initials: K
authors.lastname: Mimura
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Izawa
authors.forename: Ayako
authors.initials: A
authors.lastname: Inoue
authors.forename: Shugo
authors.initials: S
authors.lastname: Shiba
authors.forename: Takanori
authors.initials: T
authors.lastname: Maruyama
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.forename: Koji
authors.initials: K
authors.lastname: Kono
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D000077341:Lapatinib; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human