Abstract 1764: Targeting nucleotide exchange to inhibit Gq/11 driver mutations in uveal melanoma

Constitutively activating mutations in the G-protein alpha subunits GNAQ(Gαq) and GNA11(Gα11) act as oncogenic drivers in over 90% of uveal (eye) melanoma (UM) tumors. We show that constitutively active Gαq and Gα11 can be targeted in UM cells by the cyclic depsipeptide FR900359 (FR). FR inhibits GDP/GTP guanine nucleotide exchange allosterically to trap constitutively active Gαq/11 in inactive GDP-bound Gαβγ heterotrimers. FR inhibits second messenger signaling, arrests proliferation and reinstates melanocytic differentiation in UM cells driven by constitutively active Gαq or Gα11. At higher doses, FR also induces apoptosis. The re-differentiation and anti-proliferative effects of FR are not seen in UM cells that lack mutations in Gαq or Gα11. FR promotes UM cell differentiation by reactivating polycomb repressive complex 2 (PRC2)-mediated gene silencing, and this re-differentiation can be blocked with an EZH2 inhibitor. The effector system regulating PRC2 downstream of constitutively active Gαq/11 in UM is currently under investigation. Preliminary data from human primary tumor samples suggest that targeting constitutively active Gαq/11 with FR could provide an important therapeutic approach for UM. Citation Format: Michael D. Onken, Carol M. Makepeace, Kevin M. Kaltenbronn, Stanley M. Kanai, Tyson D. Todd, Shiqi Wang, Thomas J. Broekelmann, Prabakar Kumar Rao, John A. Cooper, Kendall J. Blumer. Targeting nucleotide exchange to inhibit Gq/11 driver mutations in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1764.