Abstract Activating mutations in GNAQ and GNA11 (known as GNAQ oncogenes), which encode constitutively active Gαq proteins, occur in ~90% of uveal melanoma (UM) and 4% of skin cutaneous melanoma (SKCM) respectively. UM is the most common primary cancer of the eye in adults, diagnosed in about 2,500 adults in the US every year. Approximately 50% of UM patients develop liver metastasis within 5-10 years after diagnosis, independently of the successful treatment of the primary lesions. There are effective therapeutic strategies for primary UM lesions, but UM metastatic disease is refractory to current chemotherapies and immune checkpoint inhibitors, and most patients with UM metastasis die within a year. The MEK inhibitor selumetinib has been recently approved for UM treatment, but MEK inhibition has nearly no impact on UM patient overall survival. To date, there are no effective treatment options for metastatic UM. We used bioinformatics approaches to identify systems vulnerabilities that can be exploited for UM treatment. Using the TCGA UM dataset (N=80) and SKCM samples that do not harbor Gαq genomic alterations (N=209) as control, (i) we first identified genes that are highly overexpressed in UM. We validated this approach by confirming that the genes over- and under-expressed in UM and Gαq-altered SKCM are highly overlapping (hyper-geometric p<1E-198 and p<1E-232 respectively). ii) We then filtered the genes for those whose inactivation leads to better patient survival in UM based on TCGA survival data. (iii) We finally used large datasets of gene essentiality and drug response screens in cancer cells to identify genes that are predicted to reduce cell viability when targeted in Gαq-expressing tumors. By filtering these genes for those that can be targeted by approved and experimental drugs (N=756), we identified 7 candidate druggable genes. Among them, the top was PTK2, which encodes a non- receptor tyrosine kinase known as FAK (focal adhesion kinase). By dissecting the Gαq signaling pathway, we found that Gαq actives FAK (p379-FAK) through a Trio-RhoA signaling pathway, independent of PLC-β regulated second messenger systems. RNA-seq of UM cells treated with a FAK inhibitor (FAKi, VS-4718) revealed that YAP gene-expression signatures were highly sensitive to FAKi. Of interest, YAP is a key regulator of cancer growth, and we have shown that YAP is highly activated by Gαq in UM, contributing to tumor growth (Cancer Cell. 2014). We found FAK regulates YAP activation by Gαq through a mechanism that involves YAP tyrosine phosphorylation on Y357. Interestingly, CRISPR-Cas9 KO of FAK and clinically relevant FAKi showed strong inhibition of UM growth in vitro and in vivo, concomitant with repression of YAP-regulated gene programs. Overall, our computational biology approach revealed that FAK may represent a novel precision therapeutic target human diseases initiated by aberrant Gαq signaling, including UM, the first identified Gαq-driven human malignancy. Citation Format: Xiaodong Feng, Damiano Rigiracciolo, Joo-Sang Lee, Huwate Yeerna, Nadia Arang, Simone Lubrano, David D. Schlaepfer, Pablo Tamayo, Eytan Ruppin, J. Silvio Gutkind. Targeting FAK inhibits YAP-dependent tumor growth in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 968.