EGFR activation is a potential determinant of primary resistance of hepatocellular carcinoma cells to sorafenib
EGFR activation is a potential determinant of primary resistance of hepatocellular carcinoma cells to sorafenib
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DOI：
10.1002/ijc.27604
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发表时间：
2012-12-15
影响因子：
6.4
通讯作者：
Galmiche, Antoine
中科院分区：
文献类型：
--
作者：
Ezzoukhry, Zakaria;Louandre, Christophe;Galmiche, Antoine
索拉非尼是目前肝细胞癌（HCC）的药物治疗参考，但目前尚不清楚索拉非尼是否在所有HCC中具有同等活性。在这里，我们的目的是探索肝癌细胞对索拉非尼反应的内在差异，以确定导致对这种治疗的原发性耐药的潜在机制。我们分析了一组六个人肝癌细胞系，并比较了暴露于索拉非尼后主要致癌激酶级联的活性、克隆形成潜力、增殖和凋亡。我们报道了肝癌细胞对索拉非尼的反应存在重要差异，并且一些细胞系对索拉非尼的作用比其他细胞系更具抗性。我们确定激活的表皮生长因子受体（EGFR）作为促进肝癌细胞对索拉非尼耐药的参数。在耐药细胞中，当EGFR被抑制时，索拉非尼的疗效增加，如使用两种化学抑制剂（厄洛替尼或吉非替尼）、针对EGFR的单克隆抗体（西妥昔单抗）和针对EGFR的RNA干扰所证明的。EGFR抑制剂和索拉非尼的组合提供了对HCC增殖的更好控制，最有可能是通过改善RAF激酶的阻断。因此，我们的研究结果证实了RAF激酶作为HCC治疗靶点的重要性，并确定EGFR是HCC细胞对索拉非尼敏感性的决定因素。我们的研究结果可能对索拉非尼治疗HCC的疗效的改善产生影响，并可能有助于在这种情况下识别预测性生物标志物。
Sorafenib is currently the medical treatment of reference for hepatocellular carcinoma (HCC), but it is not known whether sorafenib is equally active in all HCC. Here, our aim was to explore intrinsic differences in the response of HCC cells to sorafenib, to identify potential mechanisms leading to primary resistance to this treatment. We analyzed a panel of six human HCC cell lines and compared the activity of the main oncogenic kinase cascades, their clonogenic potential, proliferation and apoptosis upon exposure to sorafenib. We report that HCC cells present important differences in their response to sorafenib, and that some cell lines are more resistant to the actions of sorafenib than others. We identify the activated epidermal growth factor receptor (EGFR) as a parameter that promotes the resistance of HCC cells to sorafenib. In resistant cells, the efficacy of sorafenib was increased when EGFR was inhibited, as was demonstrated using two chemical inhibitors (erlotinib or gefitinib), a monoclonal antibody directed against EGFR (cetuximab), and RNA interference directed against EGFR. A combination of EGFR inhibitors and sorafenib affords a better control over HCC proliferation, most likely through an improved blockade of the RAF kinases. Our findings therefore confirm the importance of RAF kinases as therapeutic targets in HCC, and identify EGFR as a determinant of the sensitivity of HCC cells to sorafenib. Our findings bear possible implications for the improvement of the efficacy of sorafenib in HCC, and might be useful for the identification of predictive biomarkers in this context.