Melanoma of the uveal tract (a region of the eye) is the most common ocular malignancy in adults and accounts for 5% of all melanomas. According to National Cancer Institute data, there are 4.3 new cases of uveal melanoma per 1,000,000 individuals in the U.S. per year. Very little is known about the initial causes and factors that contribute to progression in this disease. Approximately, 2,000 adults are diagnosed every year. Uveal melanomas are very aggressive cancers. Half of patients will develop metastasis within 15 years of diagnosis. Uveal melanomas typically metastasize to the liver and are invariably fatal. Despite recent breakthrough in cutaneous melanoma, there are no U.S. Food and Drug-approved (FDA) targeted therapies for uveal melanoma. A glimmer of promise has been provided by targeted therapeutic agents known as MEK inhibitors, but additional therapeutic agents must be added to a MEK inhibitor regimen to enhance the response rates and provide more durable effects in patients. This application will analyze ways in which the anti-tumor action of MEK inhibitors may be enhanced in uveal melanoma. At Thomas Jefferson University, we have access to unique uveal melanoma resources and a large patient population. Additionally, we are collaborating with others in the field to promote multi-institutional efforts. At the completion of our experiments, we expect to have identified resistance-promoting mechanisms to targeted inhibitors and provide the basis for the design of new therapeutic strategies for metastatic uveal melanoma.