AMG 337 inhibits growth of MET-dependent cancer models

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 <i>MET</i>-amplified. Additional studies examining the effects of AMG 337 on the proliferation of a limited panel of cell lines with varying <i>MET</i> copy numbers revealed that high-level focal <i>MET</i> amplification (>12 copies), was required to confer <i>MET</i> oncogene addiction and AMG 337 sensitivity. One <i>MET</i>-amplified cell line, H1573 (>12 copies), was AMG 337-insensitive, possibly because of a downstream G12A KRAS mutation. Mechanism-of-action studies in sensitive <i>MET</i>-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.

from Cancer via ola Kala on Inoreader http://ift.tt/1qYw8G1
via IFTTT