Targeting nucleotide exchange to inhibit constitutively active G protein alpha-subunits in cancer

Constitutively active G protein α-subunits cause cancer, cholera, Sturge-Weber Syndrome, and other disorders. Therapeutic intervention by targeted inhibition of constitutively active Gα subunits in these disorders has yet to be achieved. Here we show that constitutively active Gαq in uveal melanoma (UM) cells can be targeted by the cyclic depsipeptide FR900359 (FR). FR allosterically inhibits GDP/GTP exchange to trap constitutively active Gαq as inactive GDP-bound Gαβγ heterotrimers. 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, reinstates melanocytic differentiation or triggers apoptosis. FR has no effect on BRAF-driven UM cells. FR promotes UM cell differentiation by re-activating polycomb repressive complex 2 (PRC2)-mediated gene silencing, a heretofore unrecognized effector system of constitutively active Gαq in UM. Constitutively active Gαq and PRC2 therefore provide therapeutic targets for UM. 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. The cyclic depsipeptide FR900359 targets nucleotide exchange to trap constitutively active mutant Gαq in the inactive GDP-bound state and uncover novel pathways and therapeutic opportunities in uveal melanoma and other diseases.