Impact of MET targeting on tumor-associated angiogenesis and growth of MET mutations-driven models of liver cancer

Abstract

Deregulated expression of the MET receptor tyrosine kinase has been reported in up to 50% of patients with hepatocellular carcinoma, the most abundant form of liver cancers, and is associated with decreased survival. Consequently, MET is considered as a molecular target in this malignancy, whose progression is highly dependent on extensive angiogenesis. Here we studied the impact of MET small molecule inhibitors on angiogenesis-associated parameters and growth of xenograft liver models consisting of cells expressing MET-mutated variants M1268T and Y1248H, which exhibit constitutive kinase activity. We demonstrate that MET mutations expression is associated with significantly increased production of vascular endothelial growth factor, which is blocked by MET targeting only in cells expressing the M1268T inhibitor-sensitive but not in the Y1248H inhibitor-resistant variant. Decrease in vascular endothelial growth factor production is also associated with reduction of tyrosine phopshorylation of the vascular endothelial growth factor receptor 2 expressed on primary liver sinusoidal endothelial cells and with inhibition of vessel formation. Furthermore, MET inhibition demonstrated an efficient anti-tumor activity and considerable reduction in microvessel density only against the M1268T-derived intrahepatic tumors. Collectively, our data support the role of targeting METassociated angiogenesis as a major biological determinant for liver tumor growth control.

AXL and MET in Hepatocellular Carcinoma: A Systematic Literature Review

“…Inhibition of MET in xenograft liver tumor models of mouse fibroblast cells (NIH3T3), which express activating MET-mutated variants (M1268T and Y1248H; constitutive kinase activity), resulted in a reduction in VEGF levels in the NIH3T3 containing the M1268T variation, but not the Y1248H variation. Inhibition of MET also revealed antitumor activity and a reduction in microvessel density in M1268T-derived intrahepatic tumors [60].…”

MET tyrosine kinase receptor expression and amplification as prognostic biomarkers of survival in gastroesophageal adenocarcinoma

“…Aberrant Met activity has been ubiquitously reported across cancers . For gastroesophageal adenocarcinoma (GEC), MET amplification and Met protein overexpression are found in 4% to 10% and 25% to 70% of GEC cases, respectively; the rates depend on the definition of positive , and the cohort studied .…”