Actionable genetic screens unveil targeting of AURKA, MEK and fatty acid metabolism as an alternative therapeutic approach for advanced melanoma

Despite the remarkable improvements achieved in the management of metastatic melanoma, there are still unmet clinical needs. A considerable fraction of patients do not respond to immune and/or targeted therapies due to primary and acquired resistance, report high-grade immune-related adverse events and lack alternative treatment options. To design effective combination therapies, we set up a functional ex vivo preclinical assay based on a drop-out genetic screen in metastatic melanoma patient-derived xenografts (PDXs). We showed that this approach can be used to isolate actionable vulnerabilities predictive of drug efficacy. In particular, we highlighted that the dual targeting of Aurora kinase A and MEK employing the combination of alisertib and trametinib (AT) is highly effective in a cohort of metastatic melanoma PDXs both ex vivo and in vivo. In particular, AT combination outperformed the standard-of-care therapy in both BRAF-mutant PDXs and in targeted therapy resistant models. Furthermore, AT treatment modulates several critical cancer pathways, including an early metabolic reprogramming which leads to the transcriptional upregulation of the fatty acid oxidation (FAO) pathway. This acquired trait unveiled an additional point of intervention for pharmacological targeting, and indeed the triple combination of AT with FAO inhibitor etomoxir proved to be further beneficial inducing tumor regression and remarkably prolonging mice overall survival.