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Uveal melanoma is the most common intraocular tumor in adults and often metastasizes to the liver, leaving patients with few options. Recurrent activating mutations in the G proteins, Gα q and Gα 11 , are observed in approximately 93% of all uveal melanomas. Although therapeutic intervention of downstream Gα q/11 targets has been unsuccessful in treating uveal melanoma, we have found that the Gα q/11 inhibitor, FR900359 (FR), effectively inhibits oncogenic Gα q/11 signaling in uveal melanoma cells expressing either mutant Gα q or Gα 11 . Inhibition of oncogenic Gα q/11 by FR results in cell-cycle arrest and induction of apoptosis. Furthermore, colony formation is prevented by FR treatment of uveal melanoma cells in 3D-cell culture, providing promise for future in vivo studies. This suggests direct inhibition of activating Gα q/11 mutants may be a potential means of treating uveal melanoma. IMPLICATIONS: Oncogenic Gα q/11 inhibition by FR900359 may be a potential treatment option for those with uveal melanoma.

Effects of Oncogenic Gαq and Gα11 Inhibition by FR900359 in Uveal Melanoma