PURPOSE: Effective chemoprevention strategies aimed at reducing lung cancer incidence are lacking. We have previously described a validated approach to the prediction of oncogenic pathway activation, using gene expression profiles (Bild A, Nature 2006). Here, we describe the relevant biology underlying the initiation and progression of lung cancer, in the context of both tumor cells and histologically normal bronchial epithelial cells.
METHODS: We analyzed available Affymetrix gene expression data obtained from histologically normal bronchial epithelial cells from never smokers (n = 41) and smokers without lung cancer (n = 69), normal bronchial epithelial cells from smokers with cancer in the contralateral lung (n = 60), as well as primary lung tumor samples from smokers (n = 87). Each dataset was analyzed using Bayesian binary regression methodologies to identify differences in the status of oncogenic signaling pathways (e.g. Ras, Src, Myc, PI3kinase, E2F) and corresponding tumor microenvironment (e.g. TNF-alpha, hypoxia).
RESULTS: In contrast to normal patients (never smokers without lung cancer), marked deregulation of all oncogenic pathways and corresponding tumor microenvironment was observed in the bronchial epithelium of smokers, regardless of lung cancer status. When normal bronchial epithelial cells from tobacco smokers with known lung cancer were compared to primary tumor cells from patients with non-small cell lung cancer, there were multiple biologically important events noted. Most notably there was increased deregulation of the Src pathway (p < 0.0001 Mann Whitney). Further, using a cohort of 17 lung cancer cell lines in cell proliferation assays, we demonstrate a significant linear relationship between activation of the Src pathway in tumor cells and response to a Src-pathway specific inhibitor (SU6656), representing a rational approach to chemopreventive strategies.
CONCLUSION: Activation of critical oncogenic pathways in normal bronchial epithelial cells after exposure to tobacco smoke, even prior to the development of malignancy confirms that smoking is a biologically distinct premalignant condition.
CLINICAL IMPLICATIONS: The ability to identify and inhibit specific deregulated oncogenic pathways may provide a novel approach to lung cancer chemoprevention.
DISCLOSURE: Richard Redman, No Financial Disclosure Information; No Product/Research Disclosure Information