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, apoptosisinducing 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.

Therapeutic potential of highly cytotoxic natural killer cells for gastric cancer

“…19,20 As expected, Lapatinib upregulated HER2 cell surface expression on both MKN7 and NCI-N87 (Supporting Information Figs. S5A and S5B).…”

Characterization of the expression and clinical features of epidermal growth factor receptor and vascular endothelial growth factor receptor-2 in esophageal carcinoma

“…VEGFR-2 is activated following stimulation with activation signals, for example binding to its ligand VEGF. A series of cascade reactions downstream of the signal transduction are initiated, enhancing gene transcription in the nucleus and promoting the proliferation and angiogenesis of vascular endothelial cells (8,13,16). Zhang et al (18) reported a xenograft model of human esophageal adenocarcinoma tissue and mouse tumor through application of neoplastic and non-neoplastic Barrett epithelial cells, confirming the aforementioned hypothesis.…”

“…Similarly, VEGFR-2 overexpression is associated with tumor progression, lymph node metastasis and poor prognosis (12,13,16). A total of 119 cases of esophageal carcinoma tissue samples from multi-ethnic patients in Xinjiang were used to evaluate the correlation between the expression of EGFR and VEGFR-2, and the results revealed a significant correlation (P<0.05).…”

Lapatinib acts on gastric cancer through both antiproliferative function and augmentation of trastuzumab-mediated antibody-dependent cellular cytotoxicity

“…Lapatinib has recently been approved by the U.S. Food and Drug Administration for the treatment of HER2-expressing advanced breast cancer [26], and lapatinib prolonged progression-free survival in patients with HER2-overexpressing advanced or metastatic breast cancer in several clinical trials [25,[27][28][29][30]. Furthermore, we and others showed that lapatinib induces the accumulation of HER2 at the cell surface and enhances the effects of trastuzumab-mediated ADCC in breast cancer and esophageal squamous cell carcinoma [31][32][33].…”