PURPOSE: MET signaling has been suggested a potential role in hepatocellular 
carcinoma (HCC) and associated with prometastasis during antiangiogenesis 
therapy. We investigated the potential association between MET expression and 
therapeutic response to sorafenib in patients with HCC. Antitumor effects of 
cabozantinib, a dual inhibitor of MET and VEGFR2, were examined in cultured HCC 
cells as well as in vivo models.
EXPERIMENTAL DESIGN: Total MET and phosphorylated MET (p-MET) were measured in 
29 resected HCC specimens, and correlated with response to sorafenib as 
postoperative adjuvant therapy. In the second set of experiments using cultured 
HCC cells, and mouse xenograft and metastatic models, effects of cabozantinib 
were examined.
RESULTS: High level of p-MET in resected HCC specimens was associated with 
resistance to adjuvant sorafenib therapy. In cultured HCC cells that expressed 
p-MET, cabozantinib inhibited the activity of MET and its downstream effectors, 
leading to G1-phase arrest. Cabozantinib inhibited tumor growth in 
p-MET-positive and p-MET-negative HCC by decreasing angiogenesis, inhibiting 
proliferation, and promoting apoptosis, but it exhibited more profound efficacy 
in p-MET-positive HCC xenografts. Cabozantinib blocked the hepatocyte growth 
factor (HGF)-stimulated MET pathway and inhibited the migration and invasion of 
the HCC cells. Notably, cabozantinib reduced the number of metastatic lesions in 
the lung and liver in the experimental metastatic mouse model.
CONCLUSIONS: Patients with HCC with high level of p-MET are associated with 
resistance to adjuvant sorafenib treatment. The dual blockade of VEGFR2 and MET 
by cabozantinib has significant antitumor activities in HCC, and the activation 
of MET in HCC may be a promising efficacy-predicting biomarker. Clin Cancer Res; 
20(11); 2959-70. ©2014 AACR.