P1.07-033 Trastuzumab Emtansine (T-DM1) Suppresses the Growth of HER2-Positive Small-Cell Lung Cancer in Preclinical Models

Abstract

To overcome chemoresistance is indispensable to bring about better prognosis in small-cell lung cancer (SCLC). We have reported that HER2 is upregulated when HER2-positive SCLC cells acquire chemoresistance. Moreover, HER2-upregulated cisplatin- or etoposide-resistant SCLC cells were sensitive to trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC). However, irinotecan-resistant SCLC cells, e.g. SBC-3/SN-38, were refractory to trastuzumab despite high HER2 expression. To address this issue, we studied the antitumor efficacy of trastuzumab emtansine (T-DM1) on trastuzumab-resistant HER2-positive SCLC. SBC-3/SN-38 (HER2-positive) or OS2RA (HER2-negative) SCLC cells were inoculated subcutaneously in the flank of six-week-old male nude mice. Tumor size was measured with a caliper two or three times per week. When tumor volume reached about 150-200 mm3, mice were randomly assigned to three treatment groups. Each group was treated with intravenous injection of T-DM1 15 mg/kg, intraperitoneal injection of trastuzumab 30 mg/kg, or saline as control. To confirm the HER2-specific delivery of T-DM1, in vivo imaging was performed. Namely, several tumor-bearing mice were intravenously administered with fluorescence-labeled T-DM1. Fluorescence images of mice were captured with IVIS® Lumina II system (PerkinElmer). Treatment with T-DM1 significantly suppressed the growth of SBC-3/SN-38 xenografts compared with trastuzumab and saline groups. Histological analysis revealed that T-DM1 remarkably induced apoptosis and inhibited proliferation. Fluorescence-labeled T-DM1 definitely accumulated to the xenografts in a HER2-selective fashion. T-DM1 treatment could be an attractive therapeutic option in trastuzumab-resistant HER2-positive SCLC where trastuzumab cannot induce enough ADCC activity. Delivery of a cytotoxic agent DM1 to the inside of cells via HER2-mediated internalization is expected and crucial to exert antitumor effect in such ADCC-lacking SCLC cells.