Overcoming chemoresistance of small-cell lung cancer through stepwise HER2-targeted antibody-dependent cell-mediated cytotoxicity and VEGF-targeted antiangiogenesis

Sci Rep. 2013;3:2669. doi: 10.1038/srep02669.

Abstract

Small-cell lung cancer (SCLC) easily recurs with a multidrug resistant phenotype. However, standard therapeutic strategies for relapsed SCLC remain unestablished. We found that human epidermal growth factor receptor 2 (HER2) is not only expressed in pretreated human SCLC specimens, but is also upregulated when HER2-positive SCLC cells acquire chemoresistance. Trastuzumab induced differential levels of antibody-dependent cell-mediated cytotoxicity (ADCC) to HER2-positive SCLC cells. Furthermore, as a mechanism of the differential levels of ADCC, we have revealed that coexpression of intracellular adhesion molecule (ICAM)-1 on SCLC cells is essential to facilitate and accelerate the trastuzumab-mediated ADCC. Although SN-38-resistant SCLC cells lacking ICAM-1 expression were still refractory to trastuzumab, their in vivo growth was significantly suppressed by bevacizumab treatment due to dependence on their distinctive and abundant production of vascular endothelial growth factor. Collectively, stepwise treatment with trastuzumab and bevacizumab is promising for the treatment of chemoresistant SCLC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Angiogenesis Inhibitors / therapeutic use
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized / metabolism
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibody-Dependent Cell Cytotoxicity / immunology
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Resistance, Neoplasm*
  • Humans
  • Immunohistochemistry
  • Intercellular Adhesion Molecule-1 / metabolism
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism*
  • Male
  • Mice
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / metabolism*
  • Small Cell Lung Carcinoma / drug therapy
  • Small Cell Lung Carcinoma / metabolism*
  • Trastuzumab
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Vascular Endothelial Growth Factor A
  • Intercellular Adhesion Molecule-1
  • Receptor, ErbB-2
  • Trastuzumab