Abstract
Despite the availability of several FDA-approved therapies, metastatic melanoma remains a significant clinical challenge, particularly for patients with brain metastases, which frequently represent the site of treatment failure and a major cause of melanoma-related mortality. Melanoma exhibits a strong propensity to metastasize to the brain, yet the molecular mechanisms driving this lethal progression remain incompletely understood, limiting the development of effective treatment options. Building on our prior discovery that focal adhesion kinase (FAK) is a key mediator of AKT1-driven brain metastasis, we sought to validate the role of FAK in melanoma progression and metastatic dissemination. Using complementary autochthonous and syngeneic mouse models of BRAF-mutant melanoma, we evaluated the impact of FAK expression on overall survival, primary tumor growth, and metastasis. Through the generation of targeted FAK mutants, we distinguished kinase-dependent from kinase-independent functions and demonstrate that FAK promotes melanoma metastasis in a kinase-dependent manner. Furthermore, we establish that FAK functions downstream of PTEN to drive metastatic progression. Collectively, these findings support the therapeutic potential of FAK inhibition, either alone or in combination with existing treatments, to more effectively combat metastatic melanoma and inform the development of emerging FAK-targeted therapies.