Analysis of the phosphatidylinosit ol 3'-kinase signaling pathway in glioblastoma patients in vivo

Abstract

Deregulated signaling through the p hosphatidylinositol 3-kinase(PI3K)pathway is common in many types of can cer,including glioblastoma.Dissecting the molecular events associated with activation of this pathway in glioblastoma p atients in vivo presents an important challenge that has implic ations for the development and clini cal testing of PI3K pathway inhibito rs.Using an immunohistochemical analysis appl ied to a tissue microarray,we performed hierarchical clustering and mul tidimensional scaling,as well as univariate and multivariate analyses,to dissect the PI3K pathway in v ivo.We demonstrate that loss of the t umor suppressor protein PTEN,which antagonizes PI3K pathwa y activation,is highly correlated w ith activation of the main PI3K effec tor Akt in vivo.We also show that Akt activation is signific antly correlated with phosphorylation of mammalian target of rapamycin(mTOR),the family of forkhead transcription factors(FOXO1,FOXO3a,and FOXO4),and S6,which are thought to promote its effects.Expression of the mutan t epidermal growth factor receptor vIII is also tightly correlated with phosphorylation of these effectors,d emonstrating an additional route to PI3K pathway activation in glioblastomas in vivo.These results provide the first dissection of the PI3K path way in glioblastoma in vivo and suggest an approach to stratifying patients for targeted kinase inhi bitor therapy