Investigating the combined inhibition of RAF, MEK, and FAK in melanoma molecular subtypes

Despite promising results from FDA-approved therapies, many patients with advanced melanoma develop resistance to standard-of-care therapy, which includes immunotherapy in all molecular subtypes and targeted therapy for BRAF V600E/K melanoma. Most melanomas harbor alterations in the mitogen-activated protein kinase (MAPK) pathway, including mutations in BRAF, NRAS, and NF1 genes. While BRAF V600E/K melanomas initially respond to mutant BRAF and MEK inhibitors, resistance develops in the majority of cases. Furthermore, there are currently no FDA-approved targeted therapies for patients with tumors harboring NRAS or NF1 alterations following immunotherapy failure. Therefore, novel and effective therapeutic approaches are urgently needed to treat these molecular subtypes of melanoma, both in primary and resistant settings. The PI3K/AKT pathway is often activated in melanoma, contributing to poor clinical outcomes and promoting brain metastases, yet clinical attempts to target this pathway have been hindered by limited efficacy or intolerable toxicity. Proteomic analysis comparing non-metastatic and metastatic primary tumors in mice revealed focal adhesion kinase (FAK) as an AKT1-specific effector and a potential alternative therapeutic target. In mutant BRAF-driven models, the combination of the FAK inhibitor VS-4718 and the RAF/MEK clamp avutometinib, with or without the mutant BRAF inhibitor encorafenib, significantly delayed tumor onset, induced regression of established tumors and brain metastases, and prolonged overall survival. These findings support an ongoing clinical trial evaluating the efficacy of avutometinib and the FAK inhibitor defactinib, with or without encorafenib, in patients with brain metastases from cutaneous melanoma (DETERMINE; NCT06194929). Early observations indicate that the triplet combination is safe and well-tolerated. Additionally, in melanoma models harboring RAS mutations or NF1 loss, the combination of VS-4718 and avutometinib significantly reduced melanoma cell growth and viability in vitro, delayed tumor progression in autochthonous mouse models, and inhibited tumor growth in patient-derived xenografts driven by these alterations. Lastly, we are investigating the non-canonical roles of FAK in modulating the tumor microenvironment to determine whether this treatment strategy alters immune cell composition, chemokine and cytokine production, and enhances the efficacy of immune checkpoint inhibition.