Targeting REV1 for the Prevention of Lung Cancer

Lung cancer is the leading cause of cancer deaths in the United States and in the world, a reflection of not only a widespread disease, but also ineffective treatment options. Therefore, novel and innovative strategies for the prevention of Jung cancer are urgently needed, one of which is proposed in this application. Lung carcinogenesis is a multi-step process from initiation to progression to metastasis driven by specific genetic alterations. Gene mutation is a major driver for genetic alterations. Mutations that activate oncogenes and inactivate tumor suppressor genes are key mechanisms of lung carcinogenesis. Thus, blocking mutagenesis will most likely disrupt carcinogenesis, achieving cancer prevention. This is a novel strategy that is proposed in this application. Tobacco smoking is the major cause of Jung cancer, and a well-known mutagen. DNA base damage-induced mutations, predominantly GT~ is a major mechanism of smoking-induced Jung cancer. Exactly how smoking-induced DNA base damage is converted into gene mutations in lung is not understood. Nevertheless, based on studies of model cell systems, the REV1-mediated mutagenesis (also known as the PoUrnutagenesis pathway) is known to be the major mechanism of base damage-induced mutagenesis. In this pathway, mutations are produced as a result of error-prone ~ranslesion synthesis, which frequently inserts a wrong base opposite the DNA lesion. It is widely hypothesized that REVI-mediated mutagenesis operates in various tissues as the major mechanism of base damage-induced mutagenesis. In yeast cells, deleting the REVI gene largely abrogates base damage-induced mutagenesis. Therefore, inhibiting REVI provides a. potentially revolutionary strategy for the prevention of lung cancer. Accordingly, we hypothesize that the REVI protein is essential for Jung carcinogenesis due to its prominent role in mutagenesis, and that inactivation of the REV1 function will block the development of lung cancer, achieving cancer prevention. The human REV1 gene was originally cloned in our laboratory. Now, we have created Revi conditional knockout mice, a project supported by a Kentucky Lung Cancer Research grant. We will use our Revi mutant transgenic mice to determine the feasibility of targeting the REV1 protein for the prevention of lung cancer. Our specific aims are (1) to prevent lung tumorigenesis by inactivating the Revi gene in the transgenic CCSP-rtTAIK-rasGl2D mouse model; and (2) to validate the hypothesis that REV1-mediated mutagenesis is a major mechanism of gene mutations in the lung. Our long-term objective is to preventing lung cancer by inhibiting REV1. Accomplishing this study will help us obtain major NIH funding for developing REVI inhibitors as therapeutic drugs for lung cancer prevention. If lung cancer can be prevented by inhibiting REV1, the contribution to human health will be enormous.