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

• DOI: 10.1038/srep02669
• Publication Date: 2013-09-16T09:09:27Z
• Authors: Toshiyuki Minami; Takashi Kijima; Satoshi Kohmo; Hisashi Arase; Yasushi Otani; Izumi Nagatomo; Ryo Takahashi; Kotaro Miyake; Masayoshi Higashi...; Osamu Morimura; Shoichi Ihara; Kazuyuki Tsujino; Haruhiko Hirata; Koji Inoue; Yoshito Takeda; Hiroshi Kida; Isao Tachibana; Atsushi Kumanogoh
• Keywords: Male; Vascular Endothelial Growth Factor A; Lung Neoplasms; Receptor, ErbB-2; Angiogenesis Inhibitors; Antineoplastic Agents; Antibodies, Monoclonal, Humanized; Article; Mice; 03 medical and health sciences; 0302 clinical medicine; Cell Line, Tumor; Animals; Humans; Antibody-Dependent Cell Cytotoxicity; Antibodies, Monoclonal; Trastuzumab; Intercellular Adhesion Molecule-1; Immunohistochemistry; Small Cell Lung Carcinoma; Xenograft Model Antitumor Assays; 3. Good health; Disease Models, Animal; Drug Resistance, Neoplasm

AbstractSmall-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.