Abstract
Trastuzumab is the only target to be approved as the first-line treatment of HER2 positive metastatic gastric cancer, but ubiquitous resistance decreases its therapeutic benefit. In this study, we found HER4, phosphorylation HER4 (p-HER4) and the mesenchymal marker Vimentin increased in trastuzumab-resistant cells (MKN45TR and NCI-N87TR), while epithelial markers expressions in trastuzumab-resistant cell lines and animal models decreased. Additionally, silencing HER4 prevented the epithelial-mesenchymal transition and led to decreased proliferation and migration in vitro and in vivo. The expression of YAP1, a vital downstream interacted target of HER4, decreased when HER4 was knocked down. Interestingly, stimulation of NRG1 could compromise the inhibitory impact and rescue cell survival; whereas, transfection of siYAP1 sensitized trastuzumab-treated cells. Expression analysis of the proteins in patient-derived xenograft model (PDX) mice showed that HER4, p-HER4, YAP1, and Vimentin were clearly upregulated in the trastuzumab-resistant mice compared to mice without trastuzumab resistance. However, HER2 and E-cadherin were downregulated in response to continuous treatment with trastuzumab. These findings elucidated that the central role of the HER4-YAP1 axis in trastuzumab resistance of HER2-positive gastric cancer cells through induction of EMT. Hence, regulating the HER4-YAP1 axis might be a promising strategy for clinical interventions in patients with HER2-positive gastric cancer.
Highlights
Gastric cancer is the fifth most commonly diagnosed malignancy and the third leading cause of cancer death worldwide [1]
Cells were exposed to increasing concentrations of trastuzumab for 8 months, and single-cell clones were isolated from a pool of resistant cells to generate the resultant cell lines
Trastuzumab cells displayed a long spindle-shaped morphology with thin, long pseudopods, which occasionally resembled finger-like pseudopods that extended from the cell bodies (Fig. 1b)
Summary
Gastric cancer is the fifth most commonly diagnosed malignancy and the third leading cause of cancer death worldwide [1]. The HER4-YAP1 axis promotes trastuzumab resistance in HER2-positive gastric cancer by inducing. A large proportion of investigations about the molecular mechanisms of trastuzumab resistance stem from breast cancer, and the generally recognized processes include hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway by PI3K alterations or PTEN loss [13,14,15]. Recent studies uncovered that growth factors act as ligands of receptor tyrosine kinases, as well as upregulation of other growth factors, such as NRG1 and HGF, which bind to HER2, can confer resistance to anti-HER2 drugs [17, 18]. The exact mechanisms of trastuzumab resistance in HER2-positive gastric cancer still remained unknown
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