Wang Zhihao, Hu Pengchao, Tang Fang, Xie Conghua
Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, People's Republic of China.
Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People's Republic of China.
Med Oncol. 2016 May;33(5):50. doi: 10.1007/s12032-016-0765-5. Epub 2016 Apr 18.
Sorafenib is a multi-targeted kinase inhibitor and has been the subject of extensive clinical research in advanced non-small cell lung cancer (NSCLC). However, sorafenib fails to improve overall survival of patients with advanced NSCLC. The molecular mechanisms that account for this phenomenon are unclear. Here we show that sorafenib treatment stabilizes epidermal growth factor receptor (EGFR) and activates EGFR pathway. Moreover, this is partly mediated by stabilization of histone deacetylase 6 (HDAC6), which has been shown to regulate EGFR endocytic trafficking and degradation. Overexpression of HDAC6 confers resistance to sorafenib in NSCLC cells. Inhibition of HDAC6 with selective inhibitors synergizes with sorafenib to kill NSCLC cells via inhibition of sorafenib-mediated EGFR pathway activation. Taken together, our findings might partly explain the failure of Phase III trial of sorafenib in improving overall survival of advanced NSCLC patients and bear possible implications for the improvement on the efficacy of sorafenib in treatment of NSCLC.
索拉非尼是一种多靶点激酶抑制剂，已成为晚期非小细胞肺癌（NSCLC）广泛临床研究的对象。然而，索拉非尼未能改善晚期NSCLC患者的总生存期。导致这种现象的分子机制尚不清楚。在此我们表明，索拉非尼治疗可稳定表皮生长因子受体（EGFR）并激活EGFR通路。此外，这部分是由组蛋白去乙酰化酶6（HDAC6）的稳定介导的，HDAC6已被证明可调节EGFR的内吞运输和降解。HDAC6的过表达赋予NSCLC细胞对索拉非尼的抗性。用选择性抑制剂抑制HDAC6可与索拉非尼协同作用，通过抑制索拉非尼介导的EGFR通路激活来杀死NSCLC细胞。综上所述，我们的发现可能部分解释了索拉非尼III期试验在改善晚期NSCLC患者总生存期方面的失败，并可能对提高索拉非尼治疗NSCLC的疗效具有启示意义。
