Recent developments of c-Met as a therapeutic target in hepatocellular carcinoma.
Recent developments of c-Met as a therapeutic target in hepatocellular carcinoma.
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DOI：
10.1002/hep.29496
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Faivre S
中科院分区：
文献类型：
--
作者：
Bouattour M;Raymond E;Qin S;Cheng AL;Stammberger U;Locatelli G;Faivre S
异常的c-Met活性与肝细胞癌（HCC）的发生有关，这表明c-Met抑制可能具有治疗潜力。然而，具有c-Met活性的非选择性激酶抑制剂（tivantinib，cabozantinib，foretinib和golvatinib）在HCC患者中的临床试验迄今未能证明显着疗效。这种缺乏观察到的疗效可能是由于几个因素，包括试验设计，缺乏根据肿瘤c-Met状态选择患者，以及这些药物的普遍脱靶活性，这可能表明c-Met抑制不完全。相比之下，选择性c-Met抑制剂（tepotinib、capmatinib）的给药水平可以达到完全抑制肿瘤c-Met活性的预期水平。此外，早期试验的结果可用于优化这些药物的临床试验设计。初步结果表明，选择性c-Met抑制剂在HCC中具有抗肿瘤活性，在Child-Pugh A肝功能患者中具有可接受的安全性和耐受性。正在进行的试验旨在评估选择性c-Met抑制剂与标准治疗相比在基于肿瘤c-Met状态选择的HCC患者中的疗效和安全性。因此，c-Met抑制仍然是HCC研究的一个活跃领域，正在进行精心设计的试验，以研究选择性c-Met抑制剂的益处。（肝病学2018;67：1132-1149）
Aberrant c‐Met activity has been implicated in the development of hepatocellular carcinoma (HCC), suggesting that c‐Met inhibition may have therapeutic potential. However, clinical trials of nonselective kinase inhibitors with c‐Met activity (tivantinib, cabozantinib, foretinib, and golvatinib) in patients with HCC have failed so far to demonstrate significant efficacy. This lack of observed efficacy is likely due to several factors, including trial design, lack of patient selection according to tumor c‐Met status, and the prevalent off‐target activity of these agents, which may indicate that c‐Met inhibition is incomplete. In contrast, selective c‐Met inhibitors (tepotinib, capmatinib) can be dosed at a level predicted to achieve complete inhibition of tumor c‐Met activity. Moreover, results from early trials can be used to optimize the design of clinical trials of these agents. Preliminary results suggest that selective c‐Met inhibitors have antitumor activity in HCC, with acceptable safety and tolerability in patients with Child‐Pugh A liver function. Ongoing trials have been designed to assess the efficacy and safety of selective c‐Met inhibition compared with standard therapy in patients with HCC that were selected based on tumor c‐Met status. Thus, c‐Met inhibition continues to be an active area of research in HCC, with well‐designed trials in progress to investigate the benefit of selective c‐Met inhibitors. (Hepatology 2018;67:1132–1149)
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发表时间：
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期刊：
Translational oncogenomics
影响因子：
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