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Gene Expr. 2018 May 18;18(2):135-147. doi: 10.3727/105221618X15174108894682. Epub 2018 Feb 6.

The Effect of Selective c-MET Inhibitor on Hepatocellular Carcinoma in the MET-Active, β-Catenin-Mutated Mouse Model.

Author information

1
Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
2
Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, P.R. China.

Abstract

Simultaneous mutations in CTNNB1 and activation of c-MET occur in 9%-12.5% of patients with hepatocellular carcinoma (HCC). Coexpression of c-MET-V5 and mutant β-catenin-Myc in mouse liver by sleeping beauty transposon/transposase and hydrodynamic tail vein injection (SB-HTVI) led to the development of HCC with 70% molecular identity to the clinical subset. Using this model, we investigated the effect of EMD1214063, a highly selective c-MET inhibitor. Five weeks after SB-HTVI when tumors were established, EMD1214063 (10 mg/kg) was administered by gastric gavage as a single agent on 5-day-on/3-day-off schedule, compared to vehicle only control. Mice were harvested at 8 or 11 weeks posttreatment. Decreased p-MET, p-AKT, p-STAT3, and p-ERK proved in vivo efficacy of EMD1214063. We observed lower Ki-67, PCNA, V5-tag, and cyclin D1 after EMD1214063 treatment only at 8 weeks. Overall, no significant differences were observed in tumor burden between the groups, although EMD1214063 marginally but significantly improved overall survival by 1.5-2 weeks. Tumors remained α-fetoprotein+, did not show any differences in inflammation, and lacked fibrosis in either group. In conclusion, c-MET inhibition alone had a minor effect on Met-β-catenin HCC at the early stages of HCC development. Thus, a single therapy with the c-MET inhibitor will be insufficient for sustained response in Met-β-catenin HCC requiring assessment of additional combinations.

PMID:
29409568
PMCID:
PMC5954626
DOI:
10.3727/105221618X15174108894682
[Indexed for MEDLINE]
Free PMC Article

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