Mutant Gq/11 Promote Uveal Melanoma Tumorigenesis by Activating YAP

Uveal melanoma (UM) is the most common cancer in adult eyes. Approximately 80% of UMs harbor somatic activating mutations in GNAQ or GNA11 (encoding Gq or G11, respectively). Herein, we show in both cell culture and human tumors that cancer-associated Gq/11 mutants activate YAP, a major effector of the Hippo tumor suppressor pathway that is also regulated by G protein-coupled receptor signaling. YAP mediates the oncogenic activity of mutant Gq/11 in UM development, and the YAP inhibitor verteporfin blocks tumor growth of UM cells containing Gq/11 mutations. This study reveals an essential role of the Hippo-YAP pathway in Gq/11-induced tumorigenesis and suggests YAP as a potential drug target for UM patients carrying mutations in GNAQ or GNA11. [Display omitted] •Uveal melanoma-associated mutant Gq/11 activates YAP•YAP activation correlates with mutations of Gq/11 in uveal melanomas•YAP is essential for mutant Gq/11-induced uveal melanoma growth•YAP inhibitor suppresses mutant Gq/11-induced uveal melanoma development Yu et al. show that uveal melanomas with GNAQ- or GNA11-activating mutations have constitutively active YAP. These tumors, but not those driven by mutant BRAF, can be suppressed by YAP inhibition, suggesting YAP as a potential therapeutic target in these tumors.