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Cancers 2014, 6(3), 1736-1752; doi:10.3390/cancers6031736

The c-Met Inhibitor MSC2156119J Effectively Inhibits Tumor Growth in Liver Cancer Models

EMD Serono, and Merck Serono Research and Development, Merck KGaA, Darmstadt 64293, Germany
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Received: 28 May 2014 / Revised: 22 July 2014 / Accepted: 31 July 2014 / Published: 19 August 2014
(This article belongs to the Special Issue MET in Cancer)
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Abstract

The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase with hepatocyte growth factor (HGF) as its only high-affinity ligand. Aberrant activation of c-Met is associated with many human malignancies, including hepatocellular carcinoma (HCC). We investigated the in vivo antitumor and antimetastatic efficacy of the c-Met inhibitor MSC2156119J (EMD 1214063) in patient-derived tumor explants. BALB/c nude mice were inoculated with MHCC97H cells or with tumor fragments of 10 patient-derived primary liver cancer explants selected according to c-Met/HGF expression levels. MSC2156119J (10, 30, and 100 mg/kg) and sorafenib (50 mg/kg) were administered orally as single-agent treatment or in combination, with vehicle as control. Tumor response, metastases formation, and alpha fetoprotein (AFP) levels were measured. MSC2156119J inhibited tumor growth and induced complete regression in mice bearing subcutaneous and orthotopic MHCC97H tumors. AFP levels were undetectable after 5 weeks of MSC2156119J treatment, and the number of metastatic lung foci was reduced. Primary liver explant models with strong c-Met/HGF activation showed increased responsiveness to MSC2156119J, with MSC2156119J showing similar or superior activity to sorafenib. Tumors characterized by low c-Met expression were less sensitive to MSC2156119J. MSC2156119J was better tolerated than sorafenib, and combination therapy did not improve efficacy. These findings indicate that selective c-Met/HGF inhibition with MSC2156119J is associated with marked regression of c-Met high-expressing tumors, supporting its clinical development as an antitumor treatment for HCC patients with active c-Met signaling. View Full-Text
Keywords: c-Met; hepatocellular carcinoma; hepatocyte growth factor; MSC2156119J; receptor tyrosine kinase; sorafenib; xenograft models c-Met; hepatocellular carcinoma; hepatocyte growth factor; MSC2156119J; receptor tyrosine kinase; sorafenib; xenograft models
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MDPI and ACS Style

Bladt, F.; Friese-Hamim, M.; Ihling, C.; Wilm, C.; Blaukat, A. The c-Met Inhibitor MSC2156119J Effectively Inhibits Tumor Growth in Liver Cancer Models. Cancers 2014, 6, 1736-1752.

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