Abstract 1193: DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, abrogates the resistance to T-DM1 in HER2-positive gastric cancer: a preclinical study

Abstract

Abstract Background Anti-HER2 therapies are beneficial for patients with HER2-positive breast and gastric cancer. T-DM1 is an HER2-targeting antibody-drug conjugate (ADC), which is structurally composed of the anti-HER2 antibody trastuzumab and the tubulin inhibitor DM1. T-DM1 has shown efficacy in patients with advanced breast cancer, but all patients eventually develop resistance to T-DM1. DS-8201a is a novel ADC composed of an anti-HER2 antibody and a novel potent topoisomerase I inhibitor DX-8951 derivative. DS-8201a achieved a high drug-to-antibody-ratio (DAR: 7-8) and homogeneous drug conjugation. The aim of this study was to elucidate the mechanisms of T-DM1 resistance, and evaluate the efficacy of DS-8201a in a T-DM1-resistant HER2-positive gastric cancer cell line. Materials and methods The T-DM1-resistant NCI-N87 cell line (N87-TDMR) was established by a step-wise method—the parent HER2-positive N87 cell line was exposed to up to 4 µg/ml of T-DM1. The profile of N87-TDMR was assessed by immunoblotting, DNA microarray, and quantitative reverse transcription-PCR (qRT-PCR). The sensitivity of parent N87 and N87-TDMR cells to T-DM1 or DS8201a was assessed by an in vitro growth inhibition assay as well as through the mouse xenograft model study. Results N87-TDMR cells were found to be resistant to T-DM1 in the in vitro growth inhibition assay (50% growth inhibitory concentration; >10 µg/ml in N87-TDMR, 0.055 µg/ml in N87) as well as in the in vivo xenograft model study, but HER2 expression was maintained in the N87-TDMR cells. A comprehensive expression analysis revealed that N87-TDMR cells showed increased ATP-binding cassette (ABC) transporter expression such as ABCC2 and ABCG2 compared with N87 cells (50.2 times; 8.0 times higher than that measured by qRT-PCR relatively). Inhibition of ABCC2 and ABCG2 by MK571 recovered the sensitivity to T-DM1 in N87-TDMR cells. Since DS-8201a has higher DAR than T-DM1 and the unique topoisomerase I inhibitor, this resistance was expected to be abrogated. DS-8201a showed anti-tumor efficacy against N87-TDMR xenograft cells in the mouse model (relative tumor growth rate: 244.2% with T-DM1, -39.2% with DS-8201a; n=10 for each treatment). Conclusions The HER2-positive gastric cancer cell line used in this preclinical study acquired resistance to T-DM1 depending on the up-regulation of ABCC2 and ABCG2 expression. However, DS-8201a could abrogate this T-DM1 resistance. These results provide a rationale for DS-8201a to be investigated for its efficacy in patients with T-DM1-resistant breast or gastric cancer. Citation Format: Yoshikane Nonagase, Naoki Takegawa, Kimio Yonesaka, Kazuko Sakai, Yusuke Ogitani, Junji Tsurutani, Kazuto Nishio, Kazuhiko Nakagawa. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, abrogates the resistance to T-DM1 in HER2-positive gastric cancer: a preclinical study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1193. doi:10.1158/1538-7445.AM2017-1193