Abstract PR09: Pharmacologic targeting of Gq reveals new pathways in uveal melanoma

Abstract

Abstract Constitutively activating mutations in GNAQ (Gαq) or GNA11 (Gα11) are the oncogenic drivers of uveal (eye) melanoma (UM), occurring in over 90% of tumors. We show that constitutively active Gαq in UM cells can be targeted by the cyclic depsipeptide FR900359 (FR). FR inhibits GDP/GTP exchange allosterically to trap constitutively active Gαq in inactive GDP-bound Gαβγ heterotrimers, and allosteric inhibition of other Gα subunits can be achieved by introduction of an FR binding site. In UM cells driven by constitutively active Gαq, FR inhibits second messenger signaling, arrests proliferation, and reinstates melanocytic differentiation. At higher doses, FR also induces apoptosis. FR has no effect on Gαq/11-wild-type UM cells. FR promotes UM cell differentiation by reactivating polycomb repressive complex 2 (PRC2)-mediated gene silencing, antagonized by a heretofore unrecognized effector system of constitutively active Gαq in UM. Constitutively active Gαq and PRC2 therefore provide important therapeutic targets for UM. Further, the development of FR analogs specific for other Gα subunit subtypes may provide novel therapeutic approaches for diseases driven by constitutively active Gα subunits or multiple G protein-coupled receptors where targeting a single receptor is ineffective. This abstract is also being presented as Poster A10. 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. Pharmacologic targeting of Gq reveals new pathways in uveal melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR09.