As shown in Figure 2, panel A B. To validate the association between the PI3K subunits and adenocarcinoma, the YTMA was employed. As opposed to the MTMA which was primarily stage I lung cancer, the YTMA included 55 stage I, and 45 stage II IV lung cancer. For the YTMA PI3K p85 and p110a subunit expression was interpretable for 163 EX 527 SEN0014196 and 168 specimens, respectively. The AQUA scores for this cohort ranged from 4.18 to 120.73 for the p85 subunit, and from 9.17 to 86.91 for the p110a subunit. Unpaired t test confirmed the findings from the MTMA, expression of the p85 subunit and the p110a subunit were significantly higher in adenocarcinomas than in squamous cell carcinomas, as shown in Figure 2, panel C D.
HDAC High p85 and p110a subunit expression correlated with advanced disease stage of disease, but not with age and gender. By Cox univariate survival analyses of continuous AQUA scores, we found that high p85 expression correlated with decreased survival. AQUA provides continuous output scores, rather than categories of,high, or,low as determined by pathologists interpreting standard immunohistochemistry. To visualize the association between continuous PI3K scores and survival, AQUA scores were dichotomized by the median, reflecting the use of routine statistical divisions in the absence of underlying justification for division of expression. Kaplan Meier survival curves were generated for PI3K p85 subunit expression and survival and P values were obtained by the Mantel Cox log rank method.
As shown in Figure 2, panel E F, we found a significant association between high p85 expression and poor survival. No association was found between p110a expression and survival. On multivariate analysis p85 expression did not retain its independent predictive value, presumably due to its association with histologic subtype and stage. The only variable associated with survival by multivariate analysis was Stage. No such association between p110a subunit expression and survival was noted. Coexpression of PI3K p85 or p110a? with mTOR in human lung tumors The association between the previously published mTOR expression and p85 and p110a subunits of PI3K was assessed. Using the Spearman rank correlation test, mTOR expression was associated with p110a expression, while no association was found between levels of mTOR and p85 subunit.
In vitro activity of NVP BKM120 and LY294002 in lung cell lines Due to the association between PI3K and advanced stage and poor survival, the in vitro activity of PI3K inhibitors was studied in six human lung cancer cell lines. Two PI3K inhibitors were utilized, we studied NVP BKM 120, a clinical quality PI3K inhibitor being developed by Novartis, and LY294002, a commercially available compound that has been widely used to study PI3K inhibition in the preclinical setting. Cells were treated with either NVP BKM120 at concentrations ranging from 0.01 nM to 8,200 nM or LY294002 at