neu naling such as through EGFR, IGF1 R and HER2 neu. There are three classes of PI3Ks. Class IA PI3K is the most widely implicated type in cancer and will be referred to as,PI3K, in the remainder of this manuscript. PI3K is a heterodimer consisting of a p85 regulatory and a p110 catalytic epigallocatechin (-)-Epigallocatechin gallate subunit. Phosphatidylinositol triphosphate mediates the activation of AKT. AKT, in turn, activates many cellular proteins involved in protein synthesis, cell growth and survival including mTOR. mTOR regulates translation by phosphorylating components of the protein synthesis machinery, including the ribosomal protein S6 kinases and 4E binding protein. Phosphorylation of 4E BP leads to the release of the translation initiation factor eIF4E which has been demonstrated to exhibit transforming and antiapoptotic activites in vitro.
PTEN reverses PI3K signaling by dephosphorylating phosphatidylinositol triphosphate. In NSCLC, PI3K AKT mTOR signaling is frequently deregulated due to mutations affecting one of its upstream regulators, the EGFR receptor, and other components within the GSK2126458 pathway. mTOR pathway components were found to be mutated in 17 genes and in more than 30 of tumors of 188 lung adenocarcinomas in which exome sequencing was performed. Increases in gene copy number of PIK3CA, the gene encoding p110a, and changes in phosphorylated AKT expression have been described in premalignant bronchial epithelial cells and NSCLC. While mutations in PIK3CA are relatively infrequent in lung cancer, PIK3CA copy number gain has been reported in 33.1 of squamous cell lung cancer and in 6.
2 adeno lung cancer in one large series. PI3K signaling has been shown to mediate bronchioalveolar stem cell expansion initiated by oncogenic K RAS. Tumor associated mutations of p110a are oncogenic in vivo in a mouse model of NSCLC. Overexpression of p85 and p110 a has been demonstrated to correlate with poor differentiation of primary lung cancers in a cohort that included 73 cases of NSCLC. Our group has previously studied the expression of mTOR in NSCLC cohorts and found an association with improved outcome. Inhibition of PI3K AKT mTOR signaling through pharmacologic and genetic approaches induces antiproliferative effects on certain NSCLC cell lines and in lung cancer mouse models. A number of PI3K inhibitors are available for preclinical research.
Older compounds like LY294002 or wortmannin have anti tumor activity in preclinical models, but their poor solubility, narrow therapeutic index and crossover inhibition of other kinases have limited their clinical application. Newer PI3K inhibitors have entered early phase clinical trials, and activity of these agents should be assessed in diseases requiring new approaches, such as NSCLC. The purpose of our study was to characterize the expression of p85 and p110 a subunits of Class IA PI3K in two large independents cohorts of NSCLC specimens and to assess the association with clinical and pathological variables including previously published