Differential responses of MET activations to MET kinase inhibitor and neutralizing antibody

BACKGROUND: 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. METHODS: With th...

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Detalles Bibliográficos
Autores principales: Kou, Jianqun, Musich, Phillip R., Staal, Ben, Kang, Liang, Qin, Yuan, Yao, Zhi Q., Zhang, Boheng, Wu, Weizhong, Tam, Angela, Huang, Alan, Hao, Huai-Xiang, Vande Woude, George F., Xie, Qian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Research
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134500/
https://www.ncbi.nlm.nih.gov/pubmed/30208970
http://dx.doi.org/10.1186/s12967-018-1628-y
Descripción
Sumario:BACKGROUND: 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. METHODS: With the goal to investigate the molecular basis of MET amplification (MET(amp)) and hepatocyte growth factor (HGF) autocrine-driven tumors in response to MET tyrosine kinase inhibitors (TKI) and neutralizing antibodies, we compared cancer cells harboring MET(amp) (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. RESULTS: We find that cancer cells driven by MET(amp) are more sensitive to INC280 than are those driven by HGF-autocrine activation. In MET(amp) cells, INC280 induced a DNA damage response with activation of repair through the p53BP1/ATM signaling pathway. Although MetMab failed to inhibit MET(amp) 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. CONCLUSIONS: Our results demonstrate that MET(amp) and HGF-autocrine activation favor different molecular mechanisms. While combining MET TKIs and ATM inhibitors may enhance the efficacy for treating tumors harboring MET(amp), a combined inhibition of MET and angiogenesis pathways may improve the therapeutic efficacy against HGF-autocrine tumors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12967-018-1628-y) contains supplementary material, which is available to authorized users.

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