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

Kou, Jianqun and Staal, Ben and Musich, Phillip and Kang, Liang and Qin, Yuan and Yao, Zhi and Zhang, Boheng and Tam, Angela and Huang, Alan and Hao, Huaixiang and Vande Woude, George and Xie, Qian (2018) Differential Therapeutic Responses of MET Oncogenic Activations to MET Kinase Inhibitor and Neutralizing Antibody. Journal of translational medicine, 16 (253 ). ISSN 1479-5876

Abstract

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.

Item Type: Article
Date Deposited: 26 Sep 2018 00:45
Last Modified: 26 Sep 2018 00:45
URI: https://oak.novartis.com/id/eprint/35139

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