Abstract
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. We sought to investigate the in vitro and in vivo antitumor activity of AMG 337, a potent and highly selective small molecule MET kinase inhibitor, in preclinical models of hepatocellular carcinoma. The antiproliferative activity of AMG 337 was evaluated across a panel of hepatocellular carcinoma cell lines in a viability assay. Daily oral administration was used to evaluate the in vivo antitumor activity of AMG 337 in two patient-derived xenograft (PDX) models of hepatocellular carcinoma (LI0612 and LI1078). AMG 337 exerted potent antiproliferative activity against 2 of 40 hepatocellular carcinoma cell lines, namely, MHCC97H (IC50, 0.015 μmol/L) and HCCLM3 (IC50, 0.025 μmol/L). Both sensitive cell lines showed MET amplification (MET/CEN-7 >2.0) assessed by FISH, and high MET expression (3+ IHC) assessed by IHC. 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 hepatocellular carcinoma PDX model LI0612 and had no effect on tumor growth in the non-MET-amplified and MET-low-expressing hepatocellular carcinoma PDX model LI1078. AMG 337 represents a promising and novel therapeutic strategy for targeting hepatocellular carcinomas with a dependence on HGF/MET signaling. Mol Cancer Ther; 15(6); 1227-37. ©2016 AACR.
Highlights
MET, a receptor for hepatocyte growth factor (HGF) is widely expressed in epithelial tissues, such as liver, lung, gastrointestinal tract, and kidney, both during embryogenesis and throughout adulthood [1]
MET gene copy number and protein expression across the 40 hepatocellular carcinoma cell line panel were analyzed by a SNP 6.0 array and ELISA assay, respectively
Both of the AMG 337-sensitive cell lines, MHCC97H and HCCLM3, had elevated MET gene copy number (Table 2) and higher protein expression compared with the other tumor cell lines displaying lack of response to AMG 337 (IC50 > 10 mmol/L; Fig. 2)
Summary
MET, a receptor for hepatocyte growth factor (HGF) is widely expressed in epithelial tissues, such as liver, lung, gastrointestinal tract, and kidney, both during embryogenesis and throughout adulthood [1]. The tyrosine phosphorylation of MET results in its activation and the recruitment of signaling effectors, such as the adaptor proteins Grb and Gab-1, which in turn promote the activation of diverse downstream signaling pathways, including the PI3K/AKT, Ras/RAF/MEK/ERK, PLC-g, FAK, and STAT3 pathways [4]. Activation of the HGF/MET signaling in cancer can occur via many different mechanisms, such as MET gene amplification, overexpression, mutation, or paracrine and autocrine activation of MET by HGF. Each of these mechanisms has been implicated in the development and progression of numerous cancers, including hepatocellular carcinoma [14,15,16,17,18]
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