Our goals are to understand the regulation and function of the Src signaling pathway in thyroid cancer to determine the most effective therapeutic strategy. Given that advanced tumors often harbor multiple genetic lesions that result in the activation of several oncogenic signaling pathways which drive tumor progression, it is likely that molecular-targeted therapies, such as Src inhibitors, will need to be combined for maximal therapeutic efficacy. Thus, the goals of this project are to define pathways that promote sensitivity versus resistance to Src inhibition. For these studies, we are using a genome-wide short inhibitory RNA (shRNA) library screen and a small molecule kinase dependency screen to identify genes and pathways that promote survival in the presence of Src inhibitors. Our goal is to identify rational therapeutic strategies that when targeted in combination with Src, will eliminate thyroid cancer cells. To further address the specific role of Src in thyroid cancer growth, invasion, and metastasis, we are using an orthotopic thyroid cancer model and a novel metastasis model. We have already shown that inhibition of Src inhibits tumor growth in an orthotopic model, and metastatic growth in an experimental metastasis model, consistent with our in vitro findings (Chan CM et al 2012). We are further validating the clinical relevance of Src signaling using a comprehensive thyroid tumor microarray. Ultimately the results from this projects will 1) allow for identification of biomarkers to better predict which tumors will respond to inhibitors of the FAK-Src pathway; 2) develop more specific targeted therapies to block distinct components of this pathway that are deregulated; and 3) develop new approaches for limiting the metastatic spread of disease.