title: Preclinical Evaluation of AMG 337, a Highly Selective Small Molecule MET Inhibitor, in Hepatocellular Carcinoma.
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.
authors.affiliation: Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd, Shanghai, China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Du
authors.affiliation: Oncology Research, Amgen Inc., Thousand Oaks, California.
authors.forename: Sean
authors.initials: S
authors.lastname: Caenepeel
authors.affiliation: Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd, Shanghai, China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Oncology Research, Amgen Inc., Thousand Oaks, California.
authors.forename: Karen
authors.initials: K
authors.lastname: Rex
authors.affiliation: Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd, Shanghai, China.
authors.forename: Yanni
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.affiliation: Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd, Shanghai, China.
authors.forename: En-Tzu
authors.initials: ET
authors.lastname: Tang
authors.affiliation: Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd, Shanghai, China.
authors.forename: Ouhong
authors.initials: O
authors.lastname: Wang
authors.affiliation: Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd, Shanghai, China.
authors.forename: Wenge
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd, Shanghai, China.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Huang
authors.affiliation: Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd, Shanghai, China.
authors.forename: Eric
authors.initials: E
authors.lastname: Huang
authors.affiliation: Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd, Shanghai, China.
authors.forename: Liaoyuan
authors.initials: L
authors.lastname: Hu
authors.affiliation: Oncology Research, Amgen Inc., Thousand Oaks, California.
authors.forename: Angela
authors.initials: A
authors.lastname: Coxon
authors.affiliation: Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd, Shanghai, China. mzhang01@amgen.com.
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics; D011728:Pyridones / Q000008:administration & dosage* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000008:administration & dosage* / Q000494:pharmacology; D014230:Triazoles / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C000609912:AMG 337; D000970:Antineoplastic Agents; D011728:Pyridones; D054852:Small Molecule Libraries; D014230:Triazoles; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met