Airway PI3K Pathway Activation Is an Early and Reversible Event in Lung Cancer Development

A cancer-associated signaling pathway is reversibly activated in the normal airways of smokers before they develop lung cancer, presenting an opportunity for preventive therapy. An Ounce of Prevention for Lung Cancer Lung cancer takes a terrific toll on humankind. Despite our understanding of the contribution of tobacco smoke, this knowledge has not been able to reverse the global increase in lung cancer incidence. New approaches are needed. Is there a way to tell whether a smoker will develop cancer and, even more important, can we see when this process starts so we can stop it? Work from Gustafson and colleagues has defined a biochemical harbinger of cancer in seemingly normal respiratory tissue that can be reversed before cancer begins. Numerous cellular signaling pathways are deregulated in cancers, such as the Ras, p53, and phosphatidylinositol 3-kinase (PI3K) pathways. A molecular understanding of lung cancer may help to develop effective drugs for deterrence. To see whether they could find a predictor of impending cancer, the authors examined normal respiratory tract tissue from smokers with lung cancer or other abnormalities. By looking for previously determined gene expression signatures for various signaling pathways, they found that one of these pathways—PI3K—was clearly activated above normal values. Moreover, the PI3K pathway was already turned on in smokers with abnormal dysplastic lesions, precursors to lung cancer. Lung cancer cells themselves showed even higher expression of the genes in the PI3K pathway. Concluding that elevated PI3K pathway activity precedes the development of lung cancer, the authors assessed gene expression in tissue from patients with dysplasias who had been successfully treated with myo-inositol, an inhibitor of PI3K, finding effective down-regulation of the PI3K pathway. Treatment of cancers with surgery, radiation, and chemotherapy—or, in some cases, targeted molecular therapies—may be the standard of care at present. But prevention should surely be the ultimate goal. The new tool reported in this article—measurement of PI3K pathway activation—and the demonstration that this is an early and reversible step in lung tumorigenesis are hopeful signs. 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.