Abstract 115: Flubendazole targets cancer stem-like properties and the HER2/Akt signaling pathway in HER2-positive breast cancer with trastuzumab resistance

Abstract

Abstract Background and Propose: HER2-positive breast cancers are associated with an aggressive phenotype and trastuzumab resistance leading to poor clinical outcomes. Flubendazole (FLU) is a potent anthelmintic agent that inhibits microtubule polymerization, and also exhibits anticancer activity in several cancer types. The objective of the present study was to investigate the effect of FLU on apoptosis, HER2/Akt signaling pathway, cancer stem cell (CSC)-like properties and trastuzumab-resistance in HER2-positive breast cancer cells. Methods: FLU-induced antitumor effects were characterized by MTS assay, Sub-G1 and G2/M-phase arrest population, Annexin-V analysis, ALDH1 activity assay, Western blotting and immunofluorescence. For in vivo study, trastuzumab-resistant JIMT1 cells were injected into the mammary fat pads of BALB/c nude mice. We then determined the tumor growth and CSC-like properties. Results and conclusion: FLU significantly reduced cell viability and induced apoptosis with accompanied by activation of caspase-3, -7, and -8, as well as PARP cleavage in HER2-positive cell lines (MDA-MB-453, SKBR3 and BT474). FLU-induced apoptosis is associated with significant decreases in expression levels of HER2, p-HER2 (Tyr1221/1222), HER3, and p-HER3 (Tyr1289). FLU treatment also resulted in G2/M-phase arrest of the cell cycle, as evidenced by a marked downregulation of phospho-Histone H3 expression. These results were closely related to the decline of CSC-like properties, coinciding with the suppression of ALDH1 activity. These effects were also observed in trastuzumab-resistant JIMT-1 cells, and significant reductions in tumor growth and ALDH1A1 downregulation were observed in xenograft models together with downregulation of HER2 expression in vivo. Our findings suggest that FLU may be potentially effective for the treatment of HER2-positive breast cancer with trastuzumab resistance. Note: This abstract was not presented at the meeting. Citation Format: Daeil Sung, Youngkwan Cho, Eunhye Oh, Tae-Min Cho, Yoon-Jae Kim, Ji Young Kim, Jae hong Seo. Flubendazole targets cancer stem-like properties and the HER2/Akt signaling pathway in HER2-positive breast cancer with trastuzumab resistance [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 115. doi:10.1158/1538-7445.AM2017-115