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

Cancer Letters
Yoon-Jae KimJi Young Kim

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,...Continue Reading

Citations

Jul 10, 2019·Journal of Experimental & Clinical Cancer Research : CR·Shichong LinChengguang Zhao
Sep 9, 2020·Immune Network·Deok-Soo SonSamuel E Adunyah
Aug 6, 2020·OncoTargets and Therapy·Xiang GaoYuxing Xu
Oct 7, 2020·Molecular Oncology·Jeremy Ariey-BonnetEddy Pasquier
Nov 17, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Xumin ZhouXiangming Mao
Jun 7, 2020·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Bárbara CostaNuno Vale
Nov 21, 2020·Neoplasia : an International Journal for Oncology Research·Zhihui ZhuHuajun Zhao
May 18, 2021·Frontiers in Oncology·Yan-Qi LiJi-Gang Dai
Sep 14, 2021·Frontiers in Cell and Developmental Biology·Xiaona XieXiaoying Huang

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