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.

Detection of MET amplification in gastroesophageal tumor specimens using IQFISH

“…The association between MET amplification and a poor prognosis in gastroesophageal cancer has also been confirmed in a recent meta-analysis (4,10). Beside the prognostics characteristics it has been suggested that MET amplification in gastroesophageal cancer potentially possess predictive properties in relation to Met targeted therapy and, thereby, could act as a companion diagnostic for some of the new therapies under development (3,11). Furthermore, in nonsmall cell lung cancer it has been suggested that MET amplification is involved with acquired resistance to EGFR tyrosine kinase inhibitors (12,13).…”

“…These specimens were collected consecutively from the screen population related to a phase II study with the investigational Met tyrosine kinase inhibitor AMG337 (Amgen, Thousand Oaks, CA, USA) (11). All specimens were anonymized with respect to the identity of the patients and no data on patient demographic was available.…”

Increased HGF Expression Induces Resistance to c-MET Tyrosine Kinase Inhibitors in Gastric Cancer

“…In many studies, it has been reported that overexpression of HGF and c-MET contributes to resistance to other therapies, such as TKIs targeting EGFR, BRAF, and HER2, as well as chemotherapy and radiotherapy (21,28). Therefore, HGF-c-MET-targeting therapies have emerged as attractive strategies, and a large number of clinical trials involving c-MET TKIs are ongoing (10,25,28). However, in the case of c-MET TKIs, the inhibitory effect is valid only in cells harboring constitutively activated c-MET (26,29).…”

“…Among c-MET-negative gastric cancer cell lines, IM95 cells are sensitive to c-MET TKIs (10). This is because IM95 cells have high expression of HGF, which triggers c-MET activation in an autocrine manner and responses to c-MET TKIs (10,30). In this study, the effect of altered HGF expression on c-MET inhibition was analyzed in terms of functional significance in gastric cancer cells.…”

A Phase 1 study evaluating AMG 337 in Asian patients with advanced solid tumors†

“…AMG 337 is a highly selective small-molecule MET inhibitor that blocks MET kinase activity (18,19). AMG 337 selectively inhibits the proliferation of MET-amplified tumor cell lines, inhibits HGFinduced MET phosphorylation and Gab-1 phosphorylation in METdependent tumor models, and reduces tumor xenograft growth in MET-amplified gastric cancer models (18,19).…”