Flubendazole overcomes trastuzumab resistance by targeting cancer stem-like properties and HER2 signaling in HER2-positive breast cancer

Yoon Jae Kim, Daeil Sung, Eunhye Oh, Youngkwan Cho, Tae Min Cho, Lee Farrand, Jae Hong Seo, Ji Young Kim

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Although trastuzumab provides significant clinical benefit for HER2-positive breast cancers, responses are limited by the 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. Flubendazole (FLU) is a potent anthelmintic agent with an exceptional safety profile. Evidence also suggests that it can act as an anticancer agent in several cancer cell types. We sought to investigate the effect of FLU on apoptosis, HER2/Akt signaling, breast cancer stem cell (BCSC)-like properties and trastuzumab resistance in HER2-positive breast cancer cells. FLU treatment induced apoptosis, associated with a significant downregulation of truncated p95HER2, phospho-HER2, phospho-HER3 and phospho-Akt levels, as well as suppression of HER2/HER3 hetero-dimerization in both trastuzumab-sensitive and –resistant lines. FLU effectively targeted BCSC-like properties including aldehyde dehydrogenase 1 (ALDH1) expression and the CD44high/CD24low phenotype, concomitant with a suppression of mammosphere-forming ability. FLU administration also caused significant tumor suppression in trastuzumab-resistant xenografts, coinciding with the downregulation of BCSC-related markers and intracellular HER2. These findings highlight the mechanisms of action of FLU in overcoming trastuzumab resistance in breast cancer.

Original languageEnglish
Pages (from-to)118-130
Number of pages13
JournalCancer Letters
Volume412
DOIs
Publication statusPublished - 2018 Jan 1

Keywords

  • Cancer stem cells
  • Flubendazole
  • HER2
  • p95HER2
  • Trastuzumab resistance

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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