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

Abstract

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 Gα₁₁, 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 Gα₁₁. 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 <i>in vivo</i> 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.