Abstract 1051: Preclinical analyses of synergistic effect of eribulin and paclitaxel for triple-negative breast cancer

Abstract

Abstract Purpose: There is an urgent need to develop novel therapeutic strategies for triple negative breast cancer (TNBC). To explore the antitumor effect of combination of eribulin (ERI) and paclitaxel (PTX) for TNBC, we conducted preclinical experiments. Materials & methods: Combinational effects of ERI and PTX were analyzed both in vitro and in vivo using two TNBC cell lines (MDA-MB-231, Hs578T). Results: When ERI was added simultaneously with PTX to TNBC cells, the sensitivity to PTX was increased synergistically. On the other hand, synergistic increase of sensitivity to ERI was observed in the presence of PTX. When the TNBC cells were treated with each drug subsequently, pretreatment with ERI for 96 hours enhanced the sensitivity to PTX administrated subsequently. In contrast, pretreatment of TNBC cells with PTX enhanced the sensitivity to the subsequently administrated ERI. When the TNBC cells were treated with ERI, the expression of epithelial marker, E-cadherin was increased, while the expression of mesenchymal markers, pSmad2, ZEB1, Slug, and vimentin were decreased. In contrast, when the cells were treated with PTX, the expressions of mesenchymal markers were increased. When epithelial-mesenchymal transition (EMT) was induced by TGF-β in the TNBC cells, the sensitivity to ERI was enhanced, while TGF-β receptor inhibitor (LY2157299) reduced the sensitivity to ERI. Furthermore, knockdown of ZEB1 by small interfering RNA conferred resistance to ERI in both TNBC cell lines. In the mouse xenograft model bearing MDA-MB-231, ERI plus PTX combination therapy significantly inhibited tumor growth compared with either PTX or ERI monotherapy. Furthermore, prior treatment with ERI significantly enhanced the antitumor activity of PTX in the mouse xenograft model. Conclusions: Our findings demonstrate an EMT-mediated synergistic antitumor effect by combination of two tubulin inhibitors. This combination therapy may serve as a novel therapeutic strategy for TNBC. Citation Format: Takaaki Oba, Ken-ichi Ito. Preclinical analyses of synergistic effect of eribulin and paclitaxel for triple-negative breast cancer [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 1051. doi:10.1158/1538-7445.AM2017-1051