Combined inhibition of focal adhesion kinase and RAF/MEK elicits synergistic inhibition of melanoma growth and reduces metastases

This study addresses the critical need for effective treatments for patients with brain metastases from cutaneous melanoma, a leading cause of therapeutic failure despite recent advancements. Using mouse models that closely replicate human melanoma brain metastases, the study explores the role of focal adhesion kinase (FAK) in metastatic progression and its potential as a therapeutic target. Pharmacological inhibition of FAK significantly reduces brain metastasis development in preclinical models. Notably, the study elucidates the interplay between FAK and the mitogen-activated protein kinase (MAPK) signaling pathway, demonstrating the enhanced efficacy of VS-4718 combined inhibition of FAK, rapidly accelerated fibrosarcoma (RAF), and mitogen-activated protein kinase kinase (MEK) in cutaneous melanoma. These findings support the clinical evaluation of the FAK inhibitor defactinib in combination with the RAF/MEK inhibitor avutometinib for patients with brain metastases from cutaneous melanoma.