Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells
Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells
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DOI：
10.1016/j.jhep.2012.02.019
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发表时间：
2012-07-01
影响因子：
25.7
通讯作者：
Desbois-Mouthon, Christele
中科院分区：
文献类型：
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作者：
Blivet-Van Eggelpoel, Marie-Jose;Chettouh, Hamza;Desbois-Mouthon, Christele
背景与目的：索拉非尼是治疗晚期肝细胞癌（HCC）的标准治疗药物。然而，在患者中观察到原发性和获得性耐药。我们研究了吉非替尼，抑制表皮生长因子受体（EGFR）和HER-3磷酸化，是否可以提高肝癌细胞对索拉非尼的反应。方法：索拉非尼和吉非替尼进行了测试，在肝癌肿瘤异种移植物和索拉非尼敏感和索拉非尼耐药肝癌细胞系。通过Western印迹和ELISA分析HER系统相关的生物标志物。RNA干扰用于下调HER系统。Amphiregulin的浓度测定通过ELISA从索拉非尼treatment.Results患者的血清中：索拉非尼与吉非替尼结合显着抑制肿瘤生长的小鼠和细胞活力降低体外相比，单一的代理商。在10%血清中培养或用EGF处理的细胞系中，索拉非尼单独抑制磷酸化STAT 3，同时维持甚至增加磷酸化ERK和/或磷酸化AKT。吉非替尼或下调EGFR和HER-3表达可预防索拉非尼的矛盾效应。在对索拉非尼具有获得性耐药的细胞中，观察到EGFR/HER-3受体的异常激活以及几种EGFR配体的过表达。这些增强的自分泌/旁分泌环导致ERK和AKT的组成性激活，并赋予对吉非替尼的敏感性增加。在索拉非尼治疗的14例患者中，有10例患者的血清双调蛋白浓度增加，观察到baseline.Conclusions：由EGFR和HER-3控制的信号通路限制索拉非尼在幼稚和索拉非尼耐药HCC细胞中的作用。因此，吉非替尼与索拉非尼合作，以增加抗增殖反应并防止耐药性。(C)2012年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Sorafenib is the standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, primary and acquired resistance is observed in patients. We examined whether gefitinib, which inhibits both epidermal growth factor receptor (EGFR) and HER-3 phosphorylation, could improve HCC cell response to sorafenib.Methods: Sorafenib and gefitinib were tested in HCC tumor xenografts and in sorafenib-sensitive and sorafenib-resistant HCC cell lines. Biomarkers relevant to the HER system were analyzed by Western blotting and ELISA. RNA interference was used to downregulate the HER system. Amphiregulin concentrations were measured by ELISA in sera from patients under sorafenib treatment.Results: Sorafenib combined with gefitinib significantly inhibited tumor growth in mice and reduced cell viability in vitro compared to single agents. In cell lines cultured in 10% serum or treated with EGF, sorafenib alone inhibited phospho-STAT3 while it maintained or even increased phospho-ERK and/or phospho-AKT. The paradoxical effects of sorafenib were prevented by gefitinib or by downregulation of EGFR and HER-3 expression. In cells with acquired resistance to sorafenib, aberrant activation of EGFR/HER-3 receptors as well as overexpression of several EGFR ligands were observed. These enhanced autocrine/paracrine loops led to the constitutive activation of ERK and AKT and conferred increased sensitivity to gefitinib. Increased serum concentrations of amphiregulin were observed in 10 out of 14 patients under sorafenib treatment compared to baselines.Conclusions: Signaling pathways controlled by EGFR and HER-3 restrict sorafenib effects both in naive and sorafenib-resistant HCC cells. Consequently, gefitinib cooperates with sorafenib to increase antiproliferative response and to prevent resistance. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.