1. In Vitro and In Vivo Activity of AMG 337, a Potent and Selective MET Kinase Inhibitor, in MET-Dependent Cancer Models
- Author
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Martin A. Broome, Jean-Christophe Harmange, Jodi Moriguchi, Hue T. Kha, Benny Amore, Michael A. Damore, Robert Radinsky, Richard Kendall, Teresa L. Burgess, Angela Coxon, Deborah Choquette, Karen Rex, Yihong Zhang, Daniel M. Baker, Jonathan Werner, Paul E. Hughes, Yajing Yang, Isabelle Dussault, Paula Kaplan-Lefko, and Sean Caenepeel
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Cancer Research ,Cell Survival ,MAP Kinase Signaling System ,Antineoplastic Agents ,Pharmacology ,03 medical and health sciences ,Mice ,Necrosis ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Humans ,Receptor ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Dose-Response Relationship, Drug ,Kinase ,Chemistry ,Gene Amplification ,Proto-Oncogene Proteins c-met ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,030104 developmental biology ,Oncology ,Mechanism of action ,Cell culture ,030220 oncology & carcinogenesis ,Phosphorylation ,Female ,medicine.symptom ,Signal Transduction - Abstract
The MET receptor tyrosine kinase is involved in cell growth, survival, and invasion. Clinical studies with small molecule MET inhibitors have shown the role of biomarkers in identifying patients most likely to benefit from MET-targeted therapy. AMG 337 is an oral, small molecule, ATP-competitive, highly selective inhibitor of the MET receptor. Herein, we describe AMG 337 preclinical activity and mechanism of action in MET-dependent tumor models. These studies suggest MET is the only therapeutic target for AMG 337. In an unbiased tumor cell line proliferation screen (260 cell lines), a closely related analogue of AMG 337, Compound 5, exhibited activity in 2 of 260 cell lines; both were MET-amplified. Additional studies examining the effects of AMG 337 on the proliferation of a limited panel of cell lines with varying MET copy numbers revealed that high-level focal MET amplification (>12 copies) was required to confer MET oncogene addiction and AMG 337 sensitivity. One MET-amplified cell line, H1573 (>12 copies), was AMG 337 insensitive, possibly because of a downstream G12A KRAS mutation. Mechanism-of-action studies in sensitive MET-amplified cell lines demonstrated that AMG 337 inhibited MET and adaptor protein Gab-1 phosphorylation, subsequently blocking the downstream PI3K and MAPK pathways. AMG 337 exhibited potency in pharmacodynamic assays evaluating MET signaling in tumor xenograft models; >90% inhibition of Gab-1 phosphorylation was observed at 0.75 mg/kg. These findings describe the preclinical activity and mechanism of action of AMG 337 in MET-dependent tumor models and indicate its potential as a novel therapeutic for the treatment of MET-dependent tumors. Mol Cancer Ther; 15(7); 1568–79. ©2016 AACR.
- Published
- 2015