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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Journal of Translational Medicine 1/2018

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

Zeitschrift:
Journal of Translational Medicine > Ausgabe 1/2018
Autoren:
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
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12967-018-1628-y) contains supplementary material, which is available to authorized users.

Abstract

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 (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.

Results

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.

Conclusions

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.
Zusatzmaterial
Additional file 1: Figure S1. INC280 alone is sufficient in inhibiting MKN45 proliferation. (A) INC280 (0.1, 1 µM) treatment for 72 hrs potently inhibited MKN45 proliferation as measured by the CellTiter-Glo assay. Further combination with ATM inhibitor Ku60019 did not improve efficacy. Data represents for Mean ± SD. Vertical bar represents the standard deviation. (B) INC280 mediated ATM signaling pathway activity in MKN45 cells.
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