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

Toshiyuki Minami; Takashi Kijima; Satoshi Kohmo; Hisashi Arase; Yasushi Otani; Izumi Nagatomo; Ryo Takahashi; Kotaro Miyake; Masayoshi Higashiguchi; Osamu Morimura; Shoichi Ihara; Kazuyuki Tsujino; Haruhiko Hirata; Koji Inoue; Yoshito Takeda; Hiroshi Kida; Isao Tachibana; Atsushi Kumanogoh

doi:10.1038/srep02669

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.

Authors

Toshiyuki Minami¹, Takashi Kijima, Satoshi Kohmo, Hisashi Arase, Yasushi Otani, Izumi Nagatomo, Ryo Takahashi, Kotaro Miyake, Masayoshi Higashiguchi, Osamu Morimura, Shoichi Ihara, Kazuyuki Tsujino, Haruhiko Hirata, Koji Inoue, Yoshito Takeda, Hiroshi Kida, Isao Tachibana, Atsushi Kumanogoh

Affiliation

¹ Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan.

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