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

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.