Effects of combined FAK inhibition with MAPK blockade in brain metastases from cutaneous melanoma - Melanoma accounts for the majority of skin cancer deaths due to its propensity to metastasize to distant organs. Since 2011, several new therapies have been FDA-approved for this disease, but brain metastases are often the cause of treatment failure. Patients with brain metastases have a dismal prognosis and despite current therapies, median overall survival is only ~one year from the time of diagnosis. Given this grim prognosis, more effective treatments are urgently needed for these patients. A major challenge in developing therapies for brain metastases has been the lack of preclinical models that develop metastases similar to the human disease. Using data obtained from human melanomas, which demonstrated increased levels of phosphorylated AKT (P-AKT) and decreased levels of PTEN in brain metastases, we generated a mouse model of melanoma with hyperactivation of AKT1 signaling that develops lung and brain metastases similar to the human disease. We used this model to delineate the mechanisms by which AKT promotes metastasis and evaluated whether this could be exploited therapeutically. Historically, the use of AKT inhibitors in melanoma clinical trials has either had limited efficacy or exhibited significant toxicity. To identify alternative targets, we used a proteomics approach and discovered that melanoma cells expressing activated AKT1 displayed elevated levels of focal adhesion (FA) factors and phosphorylated focal adhesion kinase (P-FAK). FAK is a non-receptor tyrosine kinase that promotes cell motility, invasion, and metastasis, and we observed that pharmacological inhibition of either AKT or FAK in vitro reduced invasion. Therefore, FAK may be a viable alternative therapeutic target that can be combined with standard of care targeted therapy (e.g., BRAF and MEK inhibition) and/or immunotherapy. In support of this, our preliminary data show that the combination of avutometinib, a novel dual RAF/MEK inhibitor, and VS-4718, an ATP-competitive FAK inhibitor, significantly reduces mutant BRAF- driven melanoma cell growth and also inhibits the growth of melanoma patient-derived xenografts (PDX) that are resistant to standard of care dabrafenib and trametinib, which target mutant BRAF and MEK, respectively. Since avutometinib binds to wild-type MEK and locks it in an inactive complex with A, B, and CRAF, we hypothesize that these compounds will be efficacious in other melanoma molecular subtypes with active MAPK signaling including those driven by mutant NRAS or loss of NF1 for which no targeted therapies exist. In addition, active FAK has been reported to promote an immunosuppressive tumor microenvironment (TME), which suggests that inhibition of FAK may improve responses to immunotherapy. The goal of this project is to test the hypothesis that combined RAF, MEK, and FAK inhibition can effectively reduce the growth of melanomas harboring NRASQ61R or loss of NF1 while at the same time stimulating an anti-tumor immune response. Importantly, this project addresses a critical unmet need for a more effective combination regimen in treatment refractory patients with brain metastases or at risk of developing brain metastases.
