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 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

Differential Therapeutic Responses of MET Oncogenic Activations to MET Kinase Inhibitor and Neutralizing Antibody

Purpose: MET inhibitors are in clinical trials against several cancer types, but the mechanisms toward vulnerability remain elusive. Here we characterized the molecular basis of MET amplification (METamp) and HGF-autocrine driven tumors in response to MET tyrosine kinase inhibitors (TKI) and neutralizing antibodies. Experimental Design: METamp (MKN45 and MHCC97H) and HGF-autocrine activation (JHH5 and U87) cells were treated by the MET kinase inhibitor (INC280) and the anti-MET monoclonal antibody (MetMab) to determine the sensitivity and biological responses in vitro. Tumor inhibition was evaluated in vivo using SCID and SCIDhgf mouse models, respectively. HGF-mediated angiogenesis was measured by using the human endothelial cells (HUVEC) tube formation assay. Results: MKN45 and MHCC97H cells are more sensitive than JHH5 and U87 cells to INC280 treatment but are unresponsive to MetMab. In METamp cells, INC280 induced a DNA damage response with activation of repair through the p53BP1/ATM signaling pathway. Although INC280 and MetMab showed a moderate inhibitory effect on JHH5 and U87 cells in vitro, both treatments potently suppressed tumor growth in mouse models. We found that HGF stimulation promotes human HUVEC cell tube formation via the Src pathway. INC280 or MetMab inhibited tube formation; thus in HGF-autocrine tumors, the endothelial cells are the secondary targets of tumor-derived HGF and MET inhibition. Conclusion: METamp and HGF-autocrine activation favor different molecular mechanisms, such as a DNA damage response or angiogenesis. Because individual types of MET oncogenic activation may respond to MET inhibitors differently, combination strategies should be developed based upon the molecular subtypes of the tumors