Neratinib induces ErbB2 ubiquitylation and endocytic degradation via HSP90 dissociation in breast cancer cells. Issue 2 (28th November 2016)

• Record Type: Journal Article
• Authors: Zhang, Yingqiu; Zhang, Jinrui; Liu, Congcong; Du, Sha; Feng, Lu; Luan, Xuelin; Zhang, Yayun; Shi, Yulin; Wang, Taishu; Wu, Yue; Cheng, Wei; Meng, Songshu; Li, Man; Liu, Han
• Is Part Of: Cancer letters. Volume 382:Issue 2(2016)
• Page Start: 176
• Page End: 185
• Publication Date: 2016-11-28
• Subjects: Neratinib -- ErbB2 -- HER2 -- Breast cancer -- Ubiquitylation -- Endocytosis; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2016.08.026
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: Tyrosine kinase inhibitors lapatinib and neratinib show opposite effects on ErbB2 levels. Both lapatinib and neratinib treatments elevate ErbB2 mRNA. Neratinib induces more potent endocytic degradation via endolysosome system than lapatinib. Neratinib triggers ErbB2 ubiquitylation through HSP90 dissociation. Abstract: Receptor tyrosine kinase ErbB2/HER2 is frequently observed to be overexpressed in human cancers, leading to over activation of downstream signaling modules. HER2 positive is a major type of breast cancer for which ErbB2 targeting is already proving to be an effective therapeutic strategy. Apart from antibodies against ErbB2, the small molecule tyrosine kinase inhibitor lapatinib has had successful clinical outcomes, and other inhibitors such as neratinib are currently undergoing clinical investigations. In this study we report the effects of lapatinib and neratinib on the mRNA and protein levels of the ErbB2 receptor. We provide evidence that neratinib-induced down regulation of ErbB2 occurs through ubiquitin-mediated endocytic sorting and lysosomal degradation. At the mechanistic level, neratinib treatment leads to HSP90 release from ErbB2 and its subsequent ubiquitylation and endocytic degradation. Our findings provide novel insights into the mechanism of ErbB2 inhibition by neratinib.