Lapatinib enhances trastuzumab-mediated antibody-dependent cellular cytotoxicity via upregulation of HER2 in malignant mesothelioma cells

Oncol Rep. 2015 Dec;34(6):2864-70. doi: 10.3892/or.2015.4314.


EGFR/HER2 are frequently expressed in MPM tissues, however, no studies have shown the clinical benefit of using EGFR/HER2-targeting drugs in patients with malignant pleural mesothelioma (MPM). It was reported that the tyrosine kinase inhibitor (TKI) lapatinib enhanced trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) in HER2-positive breast cancer, suggesting that this combination is a promising strategy for MPM treatment. The aim of the present study was to explore the possibility of a TKI combined with trastuzumab to enhance ADCC in MPM cells. Five MPM cell lines were used to test the effects of TKIs targeting EGFR (gefitinib, afatinib and lapatinib) on cell proliferation and the expression of the HER family receptor. The combined effects of TKI with trastuzumab on ADCC were evaluated using the LDH release assay. Additionally, MPM cells were isolated from patients and evaluated for lapatinib-induced upregulation of HER family receptors and trastuzumab- or cetuximab‑mediated ADCC. In MPM cell lines, HER2 expression was upregulated by lapatinib, downregulated by afatinib and unaffected by gefitinib. As expected, more trastuzumab bound to MPM cells pretreated with lapatinib than untreated cells, resulting in the enhancement of trastuzumab-mediated ADCC in MPM cells. In patient-derived MPM cells, both HER2 and EGFR were upregulated by lapatinib, resulting in the enhancement of both trastuzumab- and cetuximab-mediated ADCC. Of the three TKIs, only lapatinib enhanced trastuzumab-mediated ADCC via the upregulation of HER2 expression in MPM cells, suggesting that sequential combination of lapatinib and trastuzumab may be a promising strategy for MPM treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / immunology
  • Antibody-Dependent Cell Cytotoxicity / drug effects
  • Antibody-Dependent Cell Cytotoxicity / immunology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cetuximab / administration & dosage
  • Cetuximab / immunology
  • ErbB Receptors / biosynthesis
  • ErbB Receptors / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lapatinib
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology
  • Mesothelioma / drug therapy*
  • Mesothelioma / immunology
  • Mesothelioma / pathology
  • Mesothelioma, Malignant
  • Mice
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / immunology
  • Quinazolines / administration & dosage*
  • Receptor, ErbB-2 / biosynthesis*
  • Trastuzumab / administration & dosage
  • Trastuzumab / immunology
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal, Humanized
  • Protein Kinase Inhibitors
  • Quinazolines
  • Lapatinib
  • EGFR protein, human
  • ERBB2 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2
  • Trastuzumab
  • Cetuximab