title: Airway PI3K pathway activation is an early and reversible event in lung cancer development.
abstract: Although only a subset of smokers develop lung cancer, we cannot determine which smokers are at highest risk for cancer development, nor do we know the signaling pathways altered early in the process of tumorigenesis in these individuals. On the basis of the concept that cigarette smoke creates a molecular field of injury throughout the respiratory tract, this study explores oncogenic pathway deregulation in cytologically normal proximal airway epithelial cells of smokers at risk for lung cancer. We observed a significant increase in a genomic signature of phosphatidylinositol 3-kinase (PI3K) pathway activation in the cytologically normal bronchial airway of smokers with lung cancer and smokers with dysplastic lesions, suggesting that PI3K is activated in the proximal airway before tumorigenesis. Further, PI3K activity is decreased in the airway of high-risk smokers who had significant regression of dysplasia after treatment with the chemopreventive agent myo-inositol, and myo-inositol inhibits the PI3K pathway in vitro. These results suggest that deregulation of the PI3K pathway in the bronchial airway epithelium of smokers is an early, measurable, and reversible event in the development of lung cancer and that genomic profiling of these relatively accessible airway cells may enable personalized approaches to chemoprevention and therapy. Our work further suggests that additional lung cancer chemoprevention trials either targeting the PI3K pathway or measuring airway PI3K activation as an intermediate endpoint are warranted.
authors.affiliation: Section of Computational Biomedicine, Department of Medicine and Pulmonary Center, Boston University Medical Center, Boston, MA 02118, USA.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Gustafson
authors.forename: Raffaella
authors.initials: R
authors.lastname: Soldi
authors.forename: Christina
authors.initials: C
authors.lastname: Anderlind
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Scholand
authors.forename: Jun
authors.initials: J
authors.lastname: Qian
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhang
authors.forename: Kendal
authors.initials: K
authors.lastname: Cooper
authors.forename: Darren
authors.initials: D
authors.lastname: Walker
authors.forename: Annette
authors.initials: A
authors.lastname: McWilliams
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Eva
authors.initials: E
authors.lastname: Szabo
authors.forename: Jerome
authors.initials: J
authors.lastname: Brody
authors.forename: Pierre P
authors.initials: PP
authors.lastname: Massion
authors.forename: Marc E
authors.initials: ME
authors.lastname: Lenburg
authors.forename: Stephen
authors.initials: S
authors.lastname: Lam
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Bild
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira
mesh_terms: D000328:Adult; D000368:Aged; D001980:Bronchi / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D015331:Cohort Studies; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007294:Inositol / Q000494:pharmacology; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011230:Precancerous Conditions / Q000201:enzymology* / Q000473:pathology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000473:pathology; D015203:Reproducibility of Results; D012907:Smoking / Q000378:metabolism / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; D007294:Inositol; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C494929:PTEN protein, human