Cabozantinib suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of VEGFR2 and MET.
OBJECTIVE
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.


METHODS
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.
Authors' Affiliations: Departments of Hepatopancreatobiliary Surgery; Endocrinology, Sun Yat-sen Memorial Hospital; Research Center of Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou; and Department of General Surgery, Zhongshan Boai Hospital, Southern Medical University, Zhongshan, China.
Qingfeng
Q
Xiang
Authors' Affiliations: Departments of Hepatopancreatobiliary Surgery; Endocrinology, Sun Yat-sen Memorial Hospital; Research Center of Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou; and Department of General Surgery, Zhongshan Boai Hospital, Southern Medical University, Zhongshan, China.
Weiqiang
W
Chen
Authors' Affiliations: Departments of Hepatopancreatobiliary Surgery; Endocrinology, Sun Yat-sen Memorial Hospital; Research Center of Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou; and Department of General Surgery, Zhongshan Boai Hospital, Southern Medical University, Zhongshan, China.
Meng
M
Ren
Authors' Affiliations: Departments of Hepatopancreatobiliary Surgery; Endocrinology, Sun Yat-sen Memorial Hospital; Research Center of Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou; and Department of General Surgery, Zhongshan Boai Hospital, Southern Medical University, Zhongshan, China.
Jingnan
J
Wang
Authors' Affiliations: Departments of Hepatopancreatobiliary Surgery; Endocrinology, Sun Yat-sen Memorial Hospital; Research Center of Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou; and Department of General Surgery, Zhongshan Boai Hospital, Southern Medical University, Zhongshan, China.
Hongwu
H
Zhang
Authors' Affiliations: Departments of Hepatopancreatobiliary Surgery; Endocrinology, Sun Yat-sen Memorial Hospital; Research Center of Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou; and Department of General Surgery, Zhongshan Boai Hospital, Southern Medical University, Zhongshan, China.
David Y B
DY
Deng
Authors' Affiliations: Departments of Hepatopancreatobiliary Surgery; Endocrinology, Sun Yat-sen Memorial Hospital; Research Center of Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou; and Department of General Surgery, Zhongshan Boai Hospital, Southern Medical University, Zhongshan, China.
Lei
L
Zhang
Authors' Affiliations: Departments of Hepatopancreatobiliary Surgery; Endocrinology, Sun Yat-sen Memorial Hospital; Research Center of Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou; and Department of General Surgery, Zhongshan Boai Hospital, Southern Medical University, Zhongshan, China.
Changzhen
C
Shang
Authors' Affiliations: Departments of Hepatopancreatobiliary Surgery; Endocrinology, Sun Yat-sen Memorial Hospital; Research Center of Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou; and Department of General Surgery, Zhongshan Boai Hospital, Southern Medical University, Zhongshan, China cyj0509@126.com changzhen_shang@163.com.
Yajin
Y
Chen
D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D000077157:Sorafenib; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D000813:Anilides; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011725:Pyridines; C558660:cabozantinib; D009536:Niacinamide; D000077157:Sorafenib; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2