The central focus of this application is to understand the role of focal adhesion kinase (FAK) in liver cancer. Hepatocellular carcinoma (HCC) is the most rapidly increasing cancer in the United States. Currently, the underlying mechanisms of HCC are not fully known. Understanding the molecular signaling pathways that drive or mediate the development of HCC is important for identifying novel therapeutic targets for preventing or treating HCC. FAK has been shown to play an important role in tumorigenesis and cancer progression in several tissues, however, the role of FAK in liver cancer remains elusive due to the lack of in vivo studies. Currently, several FAK inhibitors are being used as promising anti-solid tumor agents in early-phase clinical trials. As most drug metabolism occurs in the liver, it s critical to understand the effect of inhibition of FAK on liver. We have found that deletion of FAK promotes steatohepatitis, hepatic fibrosis and hepatic proliferation in hepatocyte-specific Phosphatase and Tensin Homolog (PTEN)-deficient mice. As steatohepatitis, hepatic fibrosis and enhanced hepatic proliferation are thought to promote liver cancer, we propose that deletion of FAK in liver promotes hepatocarcinogenesis in hepatocyte- specific PTEN-deficient mice model. We then intend to understand the role of FAK in hepatocarcinogenesis in which activation of FAK is not due to loss of PTEN. To achieve this goal, we plan to use a carcinogen, diethylnitrosamine(DEN)-induced HCC mouse model in which activation of FAK is not due to loss of PTEN. This study will provide new insights into the role of FAK in liver cancer, which is important for treating either liver cancer or other types of cancers by targeting FAK.
FAK inhibitors are now used as promising anti-solid tumor agents in early-phase clinical trials. As most drug metabolism occurs in the liver, it is critical o understand the effect of inhibition of FAK on the liver. In this project, we intend to determine th role of FAK in hepatocarcinogenesis by two liver tumor models. The results from this project will help reveal the role of FAK in hepatocarcinogenesis in vivo, which is critical for treating cancer by targeting FAK.