Yale University School of Medicine & Yale Comprehensive Cancer, New Haven, Connecticut, United States of America.
PLoS One. 2012;7(2):e31331. doi: 10.1371/journal.pone.0031331. Epub 2012 Feb 15.
We assessed expression of p85 and p110α PI3K subunits in non-small cell lung cancer (NSCLC) specimens and the association with mTOR expression, and studied effects of targeting the PI3K/AKT/mTOR pathway in NSCLC cell lines.
Using Automated Quantitative Analysis we quantified expression of PI3K subunits in two cohorts of 190 and 168 NSCLC specimens and correlated it with mTOR expression. We studied effects of two PI3K inhibitors, LY294002 and NVP-BKM120, alone and in combination with rapamycin in 6 NSCLC cell lines. We assessed activity of a dual PI3K/mTOR inhibitor, NVP-BEZ235 alone and with an EGFR inhibitor.
p85 and p110α tend to be co-expressed (p<0.001); p85 expression was higher in adenocarcinomas than squamous cell carcinomas. High p85 expression was associated with advanced stage and poor survival. p110α expression correlated with mTOR (ρ = 0.276). In six NSCLC cell lines, addition of rapamycin to LY294002 or NVP-BKM120 was synergistic. Even very low rapamycin concentrations (1 nM) resulted in sensitization to PI3K inhibitors. NVP-BEZ235 was highly active in NSCLC cell lines with IC(50)s in the nanomolar range and resultant down-regulation of pAKT and pP70S6K. Adding Erlotinib to NVP-BEZ235 resulted in synergistic growth inhibition.
The association between PI3K expression, advanced stage and survival in NSCLC suggests that it might be a valuable drug target. Concurrent inhibition of PI3K and mTOR is synergistic in vitro, and a dual PI3K/mTOR inhibitor was highly active. Adding EGFR inhibition resulted in further growth inhibition. Targeting the PI3K/AKT/mTOR pathway at multiple levels should be tested in clinical trials for NSCLC.
我们评估了非小细胞肺癌（NSCLC）标本中 p85 和 p110αPI3K 亚基的表达及其与 mTOR 表达的关系，并研究了针对 NSCLC 细胞系中的 PI3K/AKT/mTOR 通路的影响。
使用自动定量分析，我们对两个队列的 190 例和 168 例 NSCLC 标本中的 PI3K 亚基表达进行了量化，并与 mTOR 表达进行了相关性分析。我们研究了两种 PI3K 抑制剂，LY294002 和 NVP-BKM120，单独使用和与雷帕霉素联合使用在 6 种 NSCLC 细胞系中的作用。我们评估了一种双重 PI3K/mTOR 抑制剂 NVP-BEZ235 单独使用和与 EGFR 抑制剂联合使用的效果。
p85 和 p110α 往往共同表达（p<0.001）；p85 表达在腺癌中高于鳞状细胞癌。高 p85 表达与晚期和预后不良相关。p110α 表达与 mTOR 相关（ρ=0.276）。在 6 种 NSCLC 细胞系中，雷帕霉素与 LY294002 或 NVP-BKM120 联合使用具有协同作用。即使是非常低的雷帕霉素浓度（1 nM）也会导致对 PI3K 抑制剂的敏感性增加。NVP-BEZ235 在 NSCLC 细胞系中具有高度活性，IC50 处于纳摩尔范围，导致 pAKT 和 pP70S6K 的下调。将厄洛替尼添加到 NVP-BEZ235 中会导致协同的生长抑制。
PI3K 表达与 NSCLC 中的晚期和生存之间的关联表明，它可能是一个有价值的药物靶点。PI3K 和 mTOR 的同时抑制在体外具有协同作用，双重 PI3K/mTOR 抑制剂具有高度活性。添加 EGFR 抑制会导致进一步的生长抑制。应在临床试验中对 NSCLC 进行针对 PI3K/AKT/mTOR 通路的多个水平的靶向治疗。
