Abstract 4363: Pharmacologic targeting of Gq reveals new pathways in uveal melanoma

Abstract

Abstract Constitutively active G protein α-subunits are oncogenic drivers of several cancers, most notably in uveal (eye) melanoma (UM), which have constitutively activating mutations in GNAQ(Gαq) or GNA11(Gα11) in over 90% of tumors. Therapeutic intervention by targeted inhibition of constitutively active Gα subunits in cancer has yet to be achieved. Here 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 BRAF-driven 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. Citation Format: Michael D. Onken, Carol M. Makepeace, Shiqi Wang, Kevin M. Kaltenbronn, Stanley M. Kanai, Tom J. Broekelmann, John A. Cooper, Kendall J. Blumer. Pharmacologic targeting of Gq reveals new pathways in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4363.