Preclinical evaluation of AMG 337, a highly selective small molecule MET inhibitor, in hepatocellular carcinoma
Menée in vitro et in vivo sur des modèles de carcinome hépatocellulaire, cette étude évalue l'activité antitumorale d'un composé appelé AMG 337, un inhibiteur de la signalisation MET
Aberrant hepatocyte growth factor (HGF)/MET signaling has been implicated in hepatocarcinogenesis, suggesting that MET may serve as an attractive therapeutic target in hepatocellular carcinoma (HCC). We sought to investigate the in vitro and in vivo anti-tumor activity of AMG 337, a potent and highly selective small molecule MET kinase inhibitor, in preclinical models of HCC. The anti-proliferative activity of AMG 337 was evaluated across a panel of HCC cell lines in a viability assay. Daily oral administration was used to evaluate the in vivo anti-tumor activity of AMG 337 in two patient-derived xenograft (PDX) models of HCC (LI0612 and LI1078). AMG 337 exerted potent anti-proliferative activity against two of 40 HCC cell lines, namely MHCC97H (IC50, 0.015 µM) and HCCLM3 (IC50, 0.025 µM). Both sensitive cell lines showed MET amplification (MET/CEN-7 >2.0) assessed by fluorescence in situ hybridization, and high MET expression (3+ IHC) assessed by immunohistochemistry. AMG 337 potently inhibited p-MET in all cell lines with detectable levels of total MET. However, the dose-dependent inhibition of downstream effectors of HGF/MET signaling, including p-GAB1, p-AKT, and p-ERK was limited to those cell lines sensitive to AMG 337 in a viability assay (MHCC97H and HCCLM3). AMG 337 significantly inhibited tumor growth at all doses tested in the MET-amplified and MET-high expressing HCC PDX model, LI0612 and had no effect on tumor growth in the non-MET-amplified and MET-low expressing HCC PDX model, LI1078. AMG 337 represents a promising and novel therapeutic strategy for targeting HCCs with a dependence on HGF/MET signaling.
http://mct.aacrjournals.org/content/early/2016/03/29/1535-7163.MCT-15-0745.abstract