Multi-level targeting of the phosphatidylinositol-3-kinase pathway in non-small cell lung cancer cells.
Multi-level targeting of the phosphatidylinositol-3-kinase pathway in non-small cell lung cancer cells.
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DOI：
10.1371/journal.pone.0031331
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Chao HH
中科院分区：
文献类型：
--
作者：
Zito CR;Jilaveanu LB;Anagnostou V;Rimm D;Bepler G;Maira SM;Hackl W;Camp R;Kluger HM;Chao HH
我们评估了p85和p110α PI 3 K亚基在非小细胞肺癌（NSCLC）标本中的表达及其与mTOR表达的相关性，并研究了靶向PI 3 K/AKT/mTOR通路在NSCLC细胞系中的作用。使用自动定量分析，我们定量了190例和168例NSCLC标本中PI 3 K亚基的表达，并将其与mTOR表达相关联。我们研究了两种PI 3 K抑制剂LY 294002和NVP-BKM 120单独使用以及与雷帕霉素联合使用对6种NSCLC细胞系的影响。我们评估了双重PI 3 K/mTOR抑制剂NVP-BEZ 235单独和与EGFR抑制剂的活性。p85和p110α有共表达的趋势（p<0.001），p85在腺癌中的表达高于鳞癌。p85高表达与晚期和生存率低相关。p110α表达与mTOR相关（ρ = 0.276）。 在六种NSCLC细胞系中，雷帕霉素与LY 294002或NVP-BKM 120的添加是协同的。即使是非常低的雷帕霉素浓度（1 nM）也会导致对PI 3 K抑制剂的敏化。NVP-BEZ 235在NSCLC细胞系中具有高度活性，IC 50在纳摩尔范围内，并导致pAKT和pP 70 S6 K的下调。将厄洛替尼添加到NVP-BEZ 235中导致协同生长抑制。PI 3 K的表达与NSCLC的晚期和生存期之间的相关性提示其可能是一个有价值的药物靶点。PI 3 K和mTOR的同时抑制在体外是协同的，并且双重PI 3 K/mTOR抑制剂是高度活性的。加入EGFR抑制导致进一步的生长抑制。应在NSCLC临床试验中测试多水平靶向PI 3 K/AKT/mTOR通路。
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 IC50s 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.