Title |
Differential responses of MET activations to MET kinase inhibitor and neutralizing antibody
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Published in |
Journal of Translational Medicine, September 2018
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DOI | 10.1186/s12967-018-1628-y |
Pubmed ID | |
Authors |
Jianqun Kou, Phillip R. Musich, Ben Staal, Liang Kang, Yuan Qin, Zhi Q. Yao, Boheng Zhang, Weizhong Wu, Angela Tam, Alan Huang, Huai-Xiang Hao, George F. Vande Woude, Qian Xie |
Abstract |
Aberrant MET tyrosine kinase signaling is known to cause cancer initiation and progression. While MET inhibitors are in clinical trials against several cancer types, the clinical efficacies are controversial and the molecular mechanisms toward sensitivity remain elusive. With the goal to investigate the molecular basis of MET amplification (METamp) and hepatocyte growth factor (HGF) autocrine-driven tumors in response to MET tyrosine kinase inhibitors (TKI) and neutralizing antibodies, we compared cancer cells harboring METamp (MKN45 and MHCCH97H) or HGF-autocrine (JHH5 and U87) for their sensitivity and downstream biological responses to a MET-TKI (INC280) and an anti-MET monoclonal antibody (MetMab) in vitro, and for tumor inhibition in vivo. We find that cancer cells driven by METamp are more sensitive to INC280 than are those driven by HGF-autocrine activation. In METamp cells, INC280 induced a DNA damage response with activation of repair through the p53BP1/ATM signaling pathway. Although MetMab failed to inhibit METamp cell proliferation and tumor growth, both INC280 and MetMab reduced HGF-autocrine tumor growth. In addition, we also show that HGF stimulation promoted human HUVEC cell tube formation via the Src pathway, which was inhibited by either INC280 or MetMab. These observations suggest that in HGF-autocrine tumors, the endothelial cells are the secondary targets MET inhibitors. Our results demonstrate that METamp and HGF-autocrine activation favor different molecular mechanisms. While combining MET TKIs and ATM inhibitors may enhance the efficacy for treating tumors harboring METamp, a combined inhibition of MET and angiogenesis pathways may improve the therapeutic efficacy against HGF-autocrine tumors. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Unknown | 2 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 2 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 17 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Bachelor | 3 | 18% |
Student > Master | 3 | 18% |
Student > Doctoral Student | 2 | 12% |
Researcher | 2 | 12% |
Student > Ph. D. Student | 1 | 6% |
Other | 2 | 12% |
Unknown | 4 | 24% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 5 | 29% |
Agricultural and Biological Sciences | 2 | 12% |
Neuroscience | 2 | 12% |
Medicine and Dentistry | 2 | 12% |
Immunology and Microbiology | 1 | 6% |
Other | 1 | 6% |
Unknown | 4 | 24% |