Airway PI3K pathway activation is an early and reversible event in lung cancer development.
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.
Gustafson
Adam M
AM
Section of Computational Biomedicine, Department of Medicine and Pulmonary Center, Boston University Medical Center, Boston, MA 02118, USA.
Soldi
Raffaella
R
Anderlind
Christina
C
Scholand
Mary Beth
MB
Qian
Jun
J
Zhang
Xiaohui
X
Cooper
Kendal
K
Walker
Darren
D
McWilliams
Annette
A
Liu
Gang
G
Szabo
Eva
E
Brody
Jerome
J
Massion
Pierre P
PP
Lenburg
Marc E
ME
Lam
Stephen
S
Bild
Andrea H
AH
Spira
Avrum
A
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
D004791:Enzyme Inhibitors; D007294:Inositol; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C494929:PTEN protein, human