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Lapatinib inhibits receptor phosphorylation and cell growth and enhances antibody‐dependent cellular cytotoxicity of EGFR‐ and HER2‐overexpressing esophageal cancer cell lines
Author(s) -
Mimura Kousaku,
Kono Koji,
Maruyama Takanori,
Watanabe Mitsuaki,
Izawa Shinichiro,
Shiba Shugo,
Mizukami Yoshiki,
Kawaguchi Yoshihiko,
Inoue Masayuki,
Kono Tetsuo,
Choudhury Aniruddha,
Kiessling Rolf,
Fujii Hideki
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25896
Subject(s) - lapatinib , cytotoxicity , cancer research , cetuximab , tyrosine kinase inhibitor , cell culture , cell growth , apoptosis , cell , tyrosine kinase , chemistry , medicine , cancer , receptor , biology , breast cancer , biochemistry , trastuzumab , colorectal cancer , in vitro , genetics
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.