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.

Identification of gene expression signature for cigarette smoke exposure response—from man to mouse

“…In line with the theory of the field of injury, molecular changes in response to smoke exposure can be detected even when no histological abnormalities are visible. [15][16][17][18][19] Sample acquisition from the primary site of exposure (e.g., the airways) is usually invasive and is therefore not convenient for exposure assessment and monitoring. As a minimally invasive alternative, peripheral blood sampling can be employed in the general population to establish systemic biomarkers.…”

IGF-1 activates the P13K/AKT signaling pathway via upregulation of secretory clusterin

“…The PI3K/AKT signaling pathway regulates several normal cellular processes including cell proliferation, survival, growth and motility processes that are critical for tumorigenesis (17)(18)(19)(20)(21).…”

Combined Application of Phosphoinositide 3-Kinase and Mammalian Target of Rapamycin Inhibitors Suppresses Cell Growth and Promotes Apoptosis in Human Lung Cancer Cell Lines

“…The PI3K pathway was an over-activated growth signaling pathway in human cancer especially in lung carcinoma (17)(18)(19). It has suggested the PI3K pathway inhibitors could use as the most recent drug targets in oncology (20).…”