title: In Vitro and In Vivo Activity of AMG 337, a Potent and Selective MET Kinase Inhibitor, in MET-Dependent Cancer Models.
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.
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Hughes
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Karen
authors.initials: K
authors.lastname: Rex
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Sean
authors.initials: S
authors.lastname: Caenepeel
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Broome
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Hue T
authors.initials: HT
authors.lastname: Kha
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Burgess
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Benny
authors.initials: B
authors.lastname: Amore
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Kaplan-Lefko
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Jodi
authors.initials: J
authors.lastname: Moriguchi
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Werner
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Damore
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Daniel
authors.initials: D
authors.lastname: Baker
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Choquette
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Radinsky
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Richard
authors.initials: R
authors.lastname: Kendall
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dussault
authors.affiliation: Amgen Inc., Thousand Oaks, California. acoxon@amgen.com.
authors.forename: Angela
authors.initials: A
authors.lastname: Coxon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005784:Gene Amplification; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009336:Necrosis; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met