Small-cell lung cancer (SCLC) accounts for approximately 15% of primary lung cancer and has the poorest outcome of all its histological types. One of the major reasons of extreme aggressiveness of SCLC is that it recurs shortly after initial therapy with multidrug resistance (MDR) phenotype. However, standard therapeutic strategy for relapsed-SCLC has not been established yet. As one of the targetable receptor tyrosine kinases, human epidermal growth factor receptor 2 (HER2) was reported to be a negative prognostic factor in extensive-disease SCLC (Micke et al. Int J Cancer. 2001;92:474-9). We found that HER2 was more frequently overexpressed in SCLC cell lines of Japanese origin (6/10) compared to those of Caucasian origin (0/3). We also detected HER2 expression in SCLC tissues in 7 out of 25 patients tested by our highly sensitive immunohistochemistry system. Moreover, we found that HER2 was upregulated when HER2-positive SCLC cells acquired MDR. Trastuzumab, a humanized monoclonal antibody against HER2, exerted differential levels of killing effect on HER2-positive parental and chemoresistant SCLC cells only when Fcγ receptor-positive natural killer (NK) cells coexisted. This result suggests that trastuzumab-induced SCLC cell-killing effect was caused mainly via antibody-dependent cell-mediated cytotoxicity (ADCC) but not via direct inhibition of HER2 signal. Among these cell lines, etoposide-resistant SCLC cells were most susceptible to trastuzumab in vitro and in vivo, and the antitumor effects of trastuzumab were not only dependent on the amount of HER2 expression on SCLC cells. We focused on cell-cell contact between SCLC cells and NK cells to determine the molecule affecting trastuzumab-mediated ADCC other than HER2. We found that intercellular adhesion molecule (ICAM)-1 was abundantly expressed on etoposide-resistant SCLC cells, and trastuzumab-mediated ADCC was canceled in the presence of an ICAM-1 functional blocking antibody. These results indicate that ICAM-1 expression on SCLC cell surface is indispensable to augment trastuzumab-mediated ADCC. Thus, trastuzumab could overcome etoposide-resistance in SCLC. On the contrary, irinotecan-resistant SCLC cells were still refractory to trastuzumab. The reason for this was thought that they not only lacked ICAM-1 expression but also came to produce abundant vascular endothelial growth factor (VEGF). Bevacizumab, a humanized monoclonal antibody against VEGF, treatment could significantly inhibit the in vivo growth of irinotecan-resistant xenografts through decreasing microvesseles in mice. These results suggest that bevacizumab-mediated antiangiogenesis is a promising therapeutic strategy to salvage irinotecan-resistance.

Collectively, targeting stepwise HER2 and VEGF could overcome MDR in SCLC and bring about a favorable outcome for patients with relapsed-SCLC.

Citation Format: Toshiyuki Minami, Takashi Kijima, Osamu Morimura, Yuhei Kinehara, Masayoshi Higashiguchi, Kotaro Miyake, Haruhiko Hirata, Yoshiko Takeuchi, Kiyoharu Fukushima, Yoshitomo Hayama, Koji Inoue, Izumi Nagatomo, Yoshito Takeda, Hiroshi Kida, Atsushi Kumanogoh. Targeting stepwise HER2 and VEGF can overcome multidrug resistance in small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4506. doi:10.1158/1538-7445.AM2014-4506