Effects of oncogenic Gα_q 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, Gaq and Ga11, are observed in approximately 93% of all uveal melanomas. Although therapeutic intervention of downstream Gaq/11 targets has been unsuccessful in treating uveal melanoma, we have found that the Gaq/11 inhibitor, FR900359 (FR), effectively inhibits oncogenic Gaq/11 signaling in uveal melanoma cells expressing either mutant Gaq or Ga11. Inhibition of oncogenic Gaq/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 Gaq/11 mutants may be a potential means of treating uveal melanoma. Implications: Oncogenic Gaq/11 inhibition by FR900359 may be a potential treatment option for those with uveal melanoma.