Morimura Osamu, Minami Toshiyuki, Kijima Takashi, Koyama Shohei, Otsuka Tomoyuki, Kinehara Yuhei, Osa Akio, Higashiguchi Masayoshi, Miyake Kotaro, Nagatomo Izumi, Hirata Haruhiko, Iwahori Kota, Takimoto Takayuki, Takeda Yoshito, Kida Hiroshi, Kumanogoh Atsushi
Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; Department of Oncology Center, Osaka University School of Medicine, Suita, Osaka, Japan.
Biochem Biophys Res Commun. 2017 Jul 8;488(4):596-602. doi: 10.1016/j.bbrc.2017.05.090. Epub 2017 May 17.
Overcoming chemoresistance is essential for achieving better prognoses in SCLC. Previously, we reported that HER2 is upregulated when HER2-positive SCLC cells acquire chemoresistance. HER2-upregulated cisplatin- or etoposide-resistant SCLC cells were sensitive to trastuzumab-mediated ADCC. However, irinotecan-resistant SCLC cells, such as SBC-3/SN-38, were refractory to trastuzumab despite high HER2 expression. To address this issue, we examined the antitumor efficacy of trastuzumab emtansine (T-DM1) on trastuzumab-resistant HER2-positive SCLC. Treatment with T-DM1 significantly suppressed the growth of SBC-3/SN-38 xenografts in mice compared with trastuzumab (P < 0.05). Histological analysis of xenografts was performed to evaluate the therapeutic effect on apoptosis, proliferation and tumor vasculature. T-DM1 monotherapy induced apoptosis in SBC-3/SN-38 xenografts to a greater extent than trastuzumab monotherapy with the apoptotic index of 3.71 ± 1.56% vs. 0.60 ± 0.32% (P < 0.05), and also inhibited the proliferation of tumor cells compared with trastuzumab with the proliferative index of 74.30 ± 5.54% vs. 80.12 ± 4.81% (P < 0.05). On the other hand, no significant difference in micro vessel density was observed between the treatment groups. In vivo imaging using fluorescence-labeled T-DM1 showed that intravenously administered T-DM1 was rapidly delivered to xenografts and continued to accumulate for several days in a HER2-selective fashion. From these findings, delivery of the cytotoxic agent DM1 into cells via HER2-mediated internalization is expected to exert antitumor effect in such ADCC-lacking SCLC cells. Collectively, T-DM1 will be a promising option for overcoming trastuzumab-resistance in HER2-upregulated SCLC.
克服化疗耐药性对于改善小细胞肺癌（SCLC）的预后至关重要。此前，我们报道过，HER2阳性的SCLC细胞获得化疗耐药性时，HER2会上调。HER2上调的顺铂或依托泊苷耐药的SCLC细胞对曲妥珠单抗介导的抗体依赖性细胞介导的细胞毒性作用（ADCC）敏感。然而，伊立替康耐药的SCLC细胞，如SBC-3/SN-38，尽管HER2表达水平高，但对曲妥珠单抗却不敏感。为了解决这个问题，我们研究了曲妥珠单抗偶联物（T-DM1）对曲妥珠单抗耐药的HER2阳性SCLC的抗肿瘤疗效。与曲妥珠单抗相比，T-DM1治疗显著抑制了小鼠体内SBC-3/SN-38异种移植瘤的生长（P < 0.05）。对异种移植瘤进行组织学分析，以评估对细胞凋亡、增殖和肿瘤脉管系统的治疗效果。T-DM1单药治疗诱导SBC-3/SN-38异种移植瘤细胞凋亡的程度大于曲妥珠单抗单药治疗，凋亡指数分别为3.71±1.56%和0.60±0.32%（P < 0.05），与曲妥珠单抗相比，T-DM1还抑制了肿瘤细胞的增殖，增殖指数分别为74.30±5.54%和80.12±4.81%（P < 0.05）。另一方面，各治疗组之间微血管密度没有显著差异。使用荧光标记的T-DM1进行体内成像显示，静脉注射的T-DM1迅速输送到异种移植瘤，并以HER2选择性方式持续积累数天。从这些发现来看，通过HER2介导的内化作用将细胞毒性药物DM1递送至细胞内，有望在这类缺乏ADCC的SCLC细胞中发挥抗肿瘤作用。总的来说，T-DM1将是克服HER2上调的SCLC中曲妥珠单抗耐药的一个有前景的选择。
