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

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

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.

Highlights

Small-cell lung cancer (SCLC) recurs with a multidrug resistant phenotype
Since human epidermal growth factor receptor 2 (HER2) expression is upregulated in chemoresistant SCLC cells[19], it is reasonable to target HER2 in SCLC patients who have become resistant to the front-line chemotherapy
Since all of the natural killer (NK) cells used as effectors in antibody-dependent cell-mediated cytotoxicity (ADCC) assay abundantly express lymphocyte function–associated antigen (LFA)-1, a heterodimer of CD11a and CD18 (Supplementary Figure 5), we evaluated the expression of its counter receptor, intracellular adhesion molecule (ICAM)-1, on target SCLC cells

Summary

Introduction

Small-cell lung cancer (SCLC) recurs with a multidrug resistant phenotype. standard therapeutic strategies for relapsed SCLC remain unestablished. Trastuzumab induced differential levels of antibody-dependent cell-mediated cytotoxicity (ADCC) to HER2-positive SCLC cells. Several mechanisms are proposed for the antitumor activity of trastuzumab, including inhibition of HER2-mediated signaling and antibody-dependent cellmediated cytotoxicity (ADCC), which is exerted through natural killer (NK) cell–initiated cancer cell lysis[15,16]. Chemoresistant SCLC cells exhibit increased susceptibility to lymphokine-activated killer cells compared to their chemosensitive counterparts[18]. Based on these observations, we presumed that HER2 is targetable by trastuzumab especially in chemoresistant HER2-positive SCLC. We evaluated the salvage therapeutic efficacy of bevacizumab, a humanized monoclonal Ab against vascular endothelial growth factor (VEGF), on trastuzumab-refractory SCLC

Methods

Results

Conclusion