Synthetic Lethal Screens Reveal Co-Targeting FAK and MEK as a Multimodal Precision Therapy for GNAQ-Driven Uveal Melanoma.

Purpose Uveal melanoma (UM) is the most common eye cancer in adults. Approximately 50% of UM patients develop metastatic UM (mUM) in the liver, even after successful treatment of the primary lesions. mUM is refractory to current chemo- and immune-therapies, and most mUM patients die within a year. UM is characterized by gain-of-function mutations in GNAQ/GNA11, encoding Gαq proteins. We have recently shown that the Gαq-oncogenic signaling circuitry involves a non-canonical pathway distinct from the classical activation of PLCβ and MEK-ERK. GNAQ promotes the activation of YAP1, a key oncogenic driver, through focal adhesion kinase (FAK), thereby identifying FAK as a druggable signaling hub downstream from GNAQ However, targeted therapies often activate compensatory resistance mechanisms leading to cancer relapse and treatment failure. Experimental design We performed a kinome-wide CRISPR-Cas9 sgRNA screen to identify synthetic lethal gene interactions that can be exploited therapeutically. Candidate adaptive resistance mechanisms were investigated by co-targeting strategies in UM and mUM in vitro and in vivo experimental systems. Results sgRNAs targeting the PKC and MEK-ERK signaling pathways were significantly depleted after FAK inhibition, with ERK activation representing a predominant resistance mechanism. Pharmacological inhibition of MEK and FAK showed remarkable synergistic growth-inhibitory effects in UM cells and exerted cytotoxic effects leading to tumor collapse in UM xenograft and liver mUM models in vivo. Conclusions: Coupling the unique genetic landscape of UM with the power of unbiased genetic screens, our studies reveal that FAK and MEK-ERK co-targeting may provide a new network-based precision therapeutic strategy for mUM treatment.