Activation of the HGF/c-MET axis promotes lenvatinib resistance in hepatocellular carcinoma cells with high c-MET expression
Activation of the HGF/c-MET axis promotes lenvatinib resistance in hepatocellular carcinoma cells with high c-MET expression
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DOI：
10.1007/s12032-020-01350-4
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发表时间：
2020-03-12
期刊：
影响因子：
3.4
通讯作者：
Zhang, Xiaohong
中科院分区：
文献类型：
--
作者：
Fu, Rongdang;Jiang, Shaotao;Zhang, Xiaohong
乐伐替尼是索拉非尼的一种期待已久的替代药物，用于晚期肝细胞癌（HCC）患者的一线靶向治疗。然而，乐伐替尼耐药也成为改善HCC患者预后的主要障碍。导致HCC中乐伐替尼耐药的潜在分子机制在很大程度上是未知的。HGF/c-MET轴激活与肿瘤进展和癌症的几个标志有关，被认为是耐药性的关键因素。在本研究中，我们关注HGF/c-MET轴在HCC细胞中介导乐伐替尼耐药的作用。我们发现，HGF降低了乐伐替尼对c-MET高表达的HCC细胞的抗增殖、促凋亡和抗侵袭作用，但对c-MET低表达的HCC细胞无显著影响。c-MET抑制剂PHA-665752使HCC细胞免于HGF诱导的乐伐替尼耐药性。此外，HGF/c-MET还激活了下游的PI 3 K/AKT和MAPK/ERK通路，促进了HCC细胞的上皮-间质转化（EMT）。总的来说，我们的研究结果表明，乐伐替尼联合c-MET抑制剂治疗可能会改善其在高c-MET表达的HCC患者中的全身治疗疗效。
Lenvatinib is a long-awaited alternative to sorafenib for the first-line targeted therapy of patients with advanced hepatocellular carcinoma (HCC). However, resistance to lenvatinib has also become a major obstacle to improving the prognosis of HCC patients. The underlying molecular mechanisms contributing to lenvatinib resistance in HCC are largely unknown. HGF/c-MET axis activation is related to tumor progression and several hallmarks of cancer and is considered as the key contributor to drug resistance. In the present study, we focused on the role of the HGF/c-MET axis in mediating lenvatinib resistance in HCC cells. We showed that HGF reduced the antiproliferative, proapoptotic, and anti-invasive effects of lenvatinib on HCC cells with high c-MET expression but did not significantly affect HCC cells with low c-MET expression. The c-MET inhibitor PHA-665752 rescued HCC cells from HGF-induced lenvatinib resistance. Furthermore, HGF/c-MET activated the downstream PI3K/AKT and MAPK/ERK pathways and promoted epithelial-mesenchymal transition (EMT) in HCC cells. Collectively, our results suggested that combining lenvatinib treatment with a c-MET inhibitor may improve its systemic therapeutic efficacy in HCC patients with high c-MET expression.