Our laboratory investigates signal transduction pathways that contribute to lung cancer therapeutic resistance and tumorigenesis. Although previous work from our laboratory described roles for other kinases such as ERK and PKC-delta in the therapeutic resistance of lung cancer cells, our most recent work has focused on the PI3K/Akt pathway. We showed that this pathway is constitutively active in the majority of lung cancer cells, and that activation of Akt promotes the survival of these cells when chemotherapy or radiation is administered. Because lung cancer is most commonly related to smoking, we extended these studies by demonstrating that primary cultures of human lung epithelial respond to tobacco components such as nicotine or a tobacco specific carcinogen by activating Akt, which promotes the survival of these cells when they are exposed to genotoxic stresses. Together, these data suggested that Akt activation is an early event in tobacco-related carcinogenesis. Based on this hypothesis, current laboratory efforts are focused on studying the mechanism and role of Akt activation during lung tumorigenesis and developing new, rationally designed Akt inhibitors, as none currently exist.

Project I. Akt activation and lung tumorigenesis. Ongoing studies include: 1. investigating the role of specific nicotinic acetylcholine receptors (nAchR) that mediate the biologic effects of nicotine and tobacco carcinogens in Akt activation; 2. studying the mechanism coupling of nAchR to Akt; 3. using microarray analysis to identify tobacco component-induced, Akt-dependent changes in gene expression during the phenotypic progression of lung epithelial cells, 3. evaluating the role of Akt activation in animal models of lung tumorigenesis, and 4. evaluating the PI3K/Akt pathway in normal, preneoplastic, and neoplastic human lung tissue.

Project II. Development of Akt inhibitors. Ongoing studies include the preclinical and clinical development of rationally designed small molecule inhibitors of Akt and of genetic approaches to inhibit Akt.

Results from these projects may yield insight into the role of Akt in lung cancer tumorigenesis, and may reveal new targets that could be exploited for lung cancer prevention. Moreover, the development of effective Akt inhibitors could be applicable to other types of cancer, as Akt activation is a common feature of many types of human cancer.

Selected Publications: