RRC ID 61696
Author Hughes PE, Rex K, Caenepeel S, Yang Y, Zhang Y, Broome MA, Kha HT, Burgess TL, Amore B, Kaplan-Lefko PJ, Moriguchi J, Werner J, Damore MA, Baker D, Choquette DM, Harmange JC, Radinsky R, Kendall R, Dussault I, Coxon A.
Title In Vitro and In Vivo Activity of AMG 337, a Potent and Selective MET Kinase Inhibitor, in MET-Dependent Cancer Models.
Journal Mol Cancer Ther
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.
Volume 15(7)
Pages 1568-79
Published 2016-7-1
DOI 10.1158/1535-7163.MCT-15-0871
PII 1535-7163.MCT-15-0871
PMID 27196782
MeSH Animals Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology* Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Disease Models, Animal Dose-Response Relationship, Drug Female Gene Amplification Humans MAP Kinase Signaling System / drug effects Mice Necrosis Neoplasms / drug therapy Neoplasms / genetics Neoplasms / metabolism Neoplasms / pathology Phosphatidylinositol 3-Kinases / metabolism Protein Kinase Inhibitors / chemistry Protein Kinase Inhibitors / pharmacology* Proto-Oncogene Proteins c-met / antagonists & inhibitors* Proto-Oncogene Proteins c-met / genetics Proto-Oncogene Proteins c-met / metabolism Signal Transduction / drug effects Xenograft Model Antitumor Assays
IF 4.856
Resource
Human and Animal Cells MKN45(RCB1001)