72 Defining the Role of Focal Adhesion Kinase in Melanoma

Faculty Mentor: Sheri Holmen (Huntsman Cancer Institute, University of Utah)

The propensity of melanoma to metastasize to distant sites, including the brain, makes it the deadliest form of skin cancer. Despite the success of new FDA-approved therapies, resulting in a decline in melanoma mortality rates over the past six years, the development of brain metastases is one of the primary causes of treatment failure. Understanding the mechanism of melanoma metastasis development will allow for novel therapeutic strategies to improve the overall survival of afflicted individuals, specifically in the case of brain metastases. Concurrent interplay signaling between the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3’- kinase/protein kinase B (PI3K/AKT) pathways has been demonstrated to lead to metastasis of melanoma. However, the use of pharmacological AKT inhibitors in melanoma clinical trials has either had limited efficacy or exhibited significant toxicity. To identify alternative targets, we used a proteomic analysis of non-metastatic and metastatic melanoma tumors and discovered that focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is a specific effector of AKT1. Therefore, we hypothesized that FAK may be sufficient to promote melanoma metastasis and may be an alternative therapeutic target. To test this hypothesis, we utilized an established autochthonous mouse model of melanoma to evaluate the effect of FAK on tumor progression and metastasis. Tumors were induced in mice through expression of activated FAK in cooperation with mutant BRAF, a gene altered in over 50% of all human melanomas, as well as loss of the tumor suppressors Cdkn2a and Pten, which are commonly silenced in melanoma. Expression of activated FAK phenocopied the expression of activated AKT1 as assessed by tumor penetrance, latency, and metastasis thereby validating our proteomic data. These results enhance our mechanistic understanding of melanoma brain metastases and suggest that FAK may be a viable therapeutic target to improve the survival of patients with metastatic melanoma.