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Mechanism of trastuzumab resistance caused by HER-2 mutation in breast carcinomas

Authors Kong X, Zhang K, Wang X, Yang X, Li Y, Zhai J, Xing Z, Qi Y, Gao R, Feng X, Wang J, Fang Y

Received 10 November 2018

Accepted for publication 23 April 2019

Published 2 July 2019 Volume 2019:11 Pages 5971—5982

DOI https://doi.org/10.2147/CMAR.S194137

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 3

Editor who approved publication: Dr Rituraj Purohit


Xiangyi Kong,1,2,* Kai Zhang,3,* Xiangyu Wang,1,4,* Xue Yang,1,* Yalun Li,5 Jie Zhai,1 Zeyu Xing,1 Yihang Qi,1 Ran Gao,1 Xiaoli Feng,6 Jing Wang,1 Yi Fang1

1Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People’s Republic of China; 2Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Harvard University, Boston, MA 02114-3117, USA; 3Department of Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People’s Republic of China; 4Department of Laboratory Medicine, Mayo Clinic, Rochester, MN 55902, USA; 5Department of Breast Surgery, Yantai Yuhuangding Hospital, Yantai 264000, People’s Republic of China; 6Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People’s Republic of China

*These authors contributed equally to this work

Background: Trastuzumab is an effective drug for the treatment of Her2-positive breast cancer. But, primary or secondary resistances to trastuzumab have become an important factor influencing the curative effect. The mechanisms of trastuzumab resistance are somewhat complex. The present work aims to explore the mechanism of trastuzumab resistance caused by HER-2 mutation in breast carcinomas.
Methods: Firstly, the HER2 wild type (WT) and HER2 mutant (HER2 Q429R, HER2 Q429H and HER2 T798M are the commonest 3 types of mutations) MCF7 cell lines were established. Cell proliferation inhibition was then assessed by the Cell Counting Kit-8 assay and BrdU assay. Transwell invasion assays were also conducted to investigate the metastatic potential influenced by the HER2 mutation. Furthermore, Western blotting and co-immunoprecipitation were conducted to detect protein levels and the physical interaction of HER2 and trastuzumab.
Results: The results showed that the mutant MCF7 cells were less sensitive to trastuzumab than the WTMCF7 cells. The mutation of HER2 almost had no influence on the expression of HER2 and the interaction of HER2 and trastuzumab. Finally, the mutation of HER2 weakened the inhibition of trastuzumab in the PI3K/AKT pathways. In addition, the inhibition of PI3K/AKT signaling-pathway increased the trastuzumab-sensitivity of HER2-mutant MCF7 cells.
Conclusions: Dysregulation of the PI3K-AKT signaling-pathway was a key mechanism inducing the trastuzumab-resistance to HER2 mutant breast cancer cells.

Keywords: HER2, trastuzumab, resistance, PI3K


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