Hong Bo, Wang Huogang, Deng Ke, Wang Wei, Dai Haiming, Yan Lui Vivian Wai, Lin Wenchu
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, P. R. China.
Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, P. R. China.
Oncotarget. 2017 Jul 4;8(63):106486-106498. doi: 10.18632/oncotarget.18984. eCollection 2017 Dec 5.
Small cell lung cancer (SCLC) is a highly malignant cancer with few targeted therapies. In the study, by mining the Cancer Cell Line Encyclopedia (CCLE) database, we found that PI3K/AKT/mTOR pathway was aberrant in 92% of SCLC cell lines. Moreover, we found that the phosphorylation level of 4E-BP1 was significantly correlated with SCLC sensitivity to RAD001 (mTOR inhibitor) and BEZ235 (PI3K/mTOR dual inhibitor). Combination of RAD001 and BEZ235 synergistically inhibited the growth of SCLC cells, which was accompanied by enhanced induction of cell cycle arrest and apoptosis. Such a combination dramatically inhibited the activation of AKT, and strongly reduced the phosphorylation of 4E-BP1 and its downstream target Mcl-1. Knock-down of Mcl-1 enhanced the growth inhibition of SCLC cells induced by RAD001 and BEZ235 co-treatment, whereas over-expression of Mcl-1 reduced the growth inhibitory effect. Furthermore, study demonstrated that the combination treatment suppressed tumor growth more effectively than RAD001 or BEZ235 treatment alone. In summary, our study suggests that combination of BEZ235 and RAD001 may be an effective regimen for SCLC treatment, and p-4E-BP1 may serve as a predictive biomarker for SCLC response to mTOR inhibitor.
小细胞肺癌（SCLC）是一种恶性程度很高的癌症，针对它的靶向治疗方法很少。在这项研究中，通过挖掘癌症细胞系百科全书（CCLE）数据库，我们发现92%的SCLC细胞系中PI3K/AKT/mTOR信号通路存在异常。此外，我们发现4E-BP1的磷酸化水平与SCLC对RAD001（mTOR抑制剂）和BEZ235（PI3K/mTOR双重抑制剂）的敏感性显著相关。RAD001和BEZ235联合使用可协同抑制SCLC细胞的生长，同时伴随着细胞周期阻滞和凋亡诱导的增强。这种联合用药显著抑制了AKT的激活，并强烈降低了4E-BP1及其下游靶点Mcl-1的磷酸化水平。敲低Mcl-1增强了RAD001和BEZ235联合处理诱导的SCLC细胞生长抑制作用，而Mcl-1的过表达则降低了生长抑制效果。此外，研究表明联合治疗比单独使用RAD001或BEZ235治疗更有效地抑制肿瘤生长。总之，我们的研究表明，BEZ235和RAD001联合使用可能是一种有效的SCLC治疗方案，p-4E-BP1可能作为SCLC对mTOR抑制剂反应的预测生物标志物。
