Sorafenib is the first approved systemic therapy for advanced hepatocellular carcinoma (HCC) and is the first-line choice in clinic. Sustained activation of receptor tyrosine kinases (RTKs) is associated with low efficacy of sorafenib in HCC. Activation of liver X receptor (LXR) has been reported to inhibit some RTKs. In this study, we found that the LXR agonist enhanced the anti-tumor activity of sorafenib in a subset of HCC cells with high LXR-β/α gene expression ratio. Mechanically, the activation of LXR suppressed sorafenib dependent recruitment of MET and epidermal growth factor receptor (EGFR) in lipid rafts through cholesterol efflux. Our findings imply that LXR agonist can serve as a potential sensitizer to enhance the anti-tumor effect of sorafenib.

中文翻译：

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肝X受体激动剂通过双重抑制MET和EGFR刺激肝细胞癌亚群对索拉非尼的敏感性。

索拉非尼是第一种被批准用于晚期肝细胞癌（HCC）的系统疗法，也是临床上的一线选择。受体酪氨酸激酶（RTKs）的持续激活与索拉非尼在肝癌中的低效力有关。据报道，肝脏X受体（LXR）的激活可抑制某些RTK。在这项研究中，我们发现LXR激动剂在具有高LXR-β/α基因表达比的HCC细胞子集中增强了索拉非尼的抗肿瘤活性。在机械上，LXR的激活通过胆固醇外流抑制了脂筏中索拉非尼依赖的MET和表皮生长因子受体（EGFR）的募集。我们的发现暗示LXR激动剂可以作为潜在的敏化剂来增强索拉非尼的抗肿瘤作用。