LAUSR

Although trastuzumab has shown a significant clinical benefit for HER2-positive breast cancers, responses are limited by the frequent emergence of resistance. Trastuzumab resistance is a multi-factorial phenomenon thought to arise from the presence of cancer stem cells and interactions between truncated p95HER2 and HER family members. Disulfiram (DSF), an anti-alcoholism drug, is known to elicit cytotoxicity in numerous cancer cell types in the presence of copper (Cu). We sought to investigate the effect of DSF on apoptosis, HER2/Akt signaling, cancer stem-like properties and trastuzumab resistance in HER2-positive breast cancer cells in vitro and in vivo. DSF/Cu treatment induced apoptosis, associated with a significant downregulation of HER2, truncated p95HER2, phospho-HER2, HER3, phospho-HER3 and phospho-Akt levels in both trastuzumab-sensitive and -resistant cell lines. This was accompanied by the eradication of cancer stem-like populations, concomitant with the suppression of aldehyde dehydrogenase 1 (ALDH1) activity and mammosphere-forming ability. DSF administration also caused significant tumor suppression in trastuzumab-resistant xenografts, coinciding with the downregulation of BCSC-related markers and intracellular HER2 in vivo. These findings highlight the mechanisms of action of DSF in overcoming trastuzumab resistance in HER2-positive breast cancer. Citation Format: Yoon-Jae Kim, Youngkwan Cho, Daeil Sung, Eunhye Oh, Tae-Min Cho, Seojin Jang, Ji Young Kim, Jae Hong Seo. Disulfiram overcomes trastuzumab resistance by targeting cancer stem-like properties and HER2/Akt signaling in HER2-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2335.