Analysis of the phosphatidylinositol 3'-kinase signaling pathway in glioblastoma patients in vivo.
Deregulated signaling through the phosphatidylinositol 3'-kinase (PI3K) pathway is common in many types of cancer, including glioblastoma. Dissecting the molecular events associated with activation of this pathway in glioblastoma patients in vivo presents an important challenge that has implications for the development and clinical testing of PI3K pathway inhibitors. Using an immunohistochemical analysis applied to a tissue microarray, we performed hierarchical clustering and multidimensional scaling, as well as univariate and multivariate analyses, to dissect the PI3K pathway in vivo. We demonstrate that loss of the tumor suppressor protein PTEN, which antagonizes PI3K pathway activation, is highly correlated with activation of the main PI3K effector Akt in vivo. We also show that Akt activation is significantly 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 mutant epidermal growth factor receptor vIII is also tightly correlated with phosphorylation of these effectors, demonstrating an additional route to PI3K pathway activation in glioblastomas in vivo. These results provide the first dissection of the PI3K pathway in glioblastoma in vivo and suggest an approach to stratifying patients for targeted kinase inhibitor therapy.
Choe
Gheeyoung
G
Departments of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
Horvath
Steve
S
Cloughesy
Timothy F
TF
Crosby
Katherine
K
Seligson
David
D
Palotie
Aarno
A
Inge
Landon
L
Smith
Bradley L
BL
Sawyers
Charles L
CL
Mischel
Paul S
PS
D001932:Brain Neoplasms / Q000201:enzymology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000096:biosynthesis; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005909:Glioblastoma / Q000201:enzymology*; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis
D004268:DNA-Binding Proteins; D066246:ErbB Receptors; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C085126:FOXO1 protein, human; C410723:epidermal growth factor receptor VIII; C546842:MTOR protein, human; C494918:AKT1 protein, human; C494929:PTEN protein, human