Targeting MET Kinase in Cancer: The Therapeutic Potential of AMG 337

The abstract discusses the role of the MET receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), in promoting cell proliferation, survival, and invasion, which is often seen in various cancers. The study introduces AMG 337, a small molecule inhibitor that is potent and highly selective for the MET kinase, showing significant activity in cancer models dependent on MET.

In enzymatic tests, AMG 337 effectively suppressed MET kinase activity with an IC50 of less than 5 nanomolar (nM). The inhibitor showed high specificity for MET, as demonstrated in a competitive binding assay against over 400 other protein and lipid kinases. In cellular assays, AMG 337 also inhibited MET phosphorylation induced by HGF with an IC50 of less than 10 nM.

The research aimed to find genomic markers that could predict the response to AMG 337 by profiling its effects on cell viability across more than 200 cancer cell lines. It was found that AMG 337 significantly affected only two gastric cancer cell lines, SNU-5 and Hs746T, which both had MET gene amplification. The IC50 for these sensitive cell lines was less than 50 nM, while it was greater than 10 micromolar (μM) in all other tested cell lines.

Further studies with a broader range of cancer cell lines from gastric, non-small cell lung cancer (NSCLC), and esophageal origins confirmed that AMG 337's anti-proliferative activity was linked to MET amplification. In these cell lines, AMG 337 treatment resulted in the inhibition of the PI3K and MAPK signaling pathways, leading to growth arrest, an increase in cells in the G1 phase of the cell cycle, a decrease in DNA synthesis, and the induction of apoptosis.

In animal models, oral administration of AMG 337 showed strong dose-dependent anti-tumor effects in gastric cancer xenografts with MET amplification, aligning with the modulation of MET signaling.

The study concludes that AMG 337 has potential as a therapeutic agent for treating tumors with dysregulated MET signaling, especially those with MET amplification. A phase 1 clinical trial is underway to assess the safety, tolerability, and pharmacokinetics of AMG 337 in patients with solid tumors.

The citation for this abstract is by Paul E. Hughes et al., highlighting AMG 337's significant growth inhibitory activity in MET-dependent cancer models. It was presented at the 105th Annual Meeting of the American Association for Cancer Research in 2014.