Cabozantinib Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by a Dual Blockade of VEGFR2 and MET
Cabozantinib Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by a Dual Blockade of VEGFR2 and MET
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卡博替尼通过双重阻断 VEGFR2 和 MET 抑制肝细胞癌中的肿瘤生长和转移
DOI：
10.1158/1078-0432.ccr-13-2620
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发表时间：
2014-06-01
影响因子：
11.5
通讯作者：
Chen, Yajin
中科院分区：
文献类型：
--
作者：
Xiang, Qingfeng;Chen, Weiqiang;Chen, Yajin
目的：MET信号传导已被认为在肝细胞癌（HCC）中发挥潜在作用，并与抗血管生成治疗期间的促转移相关。我们研究了肝癌患者MET表达与索拉非尼治疗反应之间的潜在相关性。在培养的HCC细胞以及体内模型中检查卡博替尼（MET和VEGFR 2的双重抑制剂）的抗肿瘤作用。实验设计：在29例切除的HCC标本中测量了总MET和磷酸化MET（p-MET），并与索拉非尼作为术后辅助治疗的反应相关。在使用培养的HCC细胞和小鼠异种移植和转移模型的第二组实验中，检查了卡博替尼的作用。结果：切除的HCC标本中高水平的p-MET与对辅助索拉非尼治疗的耐药相关。在表达p-MET的培养HCC细胞中，卡博替尼抑制MET及其下游效应物的活性，导致G1期阻滞。卡博替尼通过减少血管生成、抑制增殖和促进凋亡来抑制p-MET阳性和p-MET阴性HCC中的肿瘤生长，但其在p-MET阳性HCC异种移植物中表现出更深刻的功效。卡博替尼阻断肝细胞生长因子（HGF）刺激的MET途径，抑制HCC细胞的迁移和侵袭。值得注意的是，卡博替尼减少了实验转移性小鼠模型中肺和肝中转移性病变的数量。结论：p-MET水平高的HCC患者对索拉非尼辅助治疗耐药。卡博替尼对VEGFR 2和MET的双重阻断在肝癌中具有显着的抗肿瘤活性，并且肝癌中MET的激活可能是一种有希望的疗效预测生物标志物。临床癌症研究; 20（11）; 2959-70。©2014 AACR.
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.