Targeting nucleotide exchange to inhibit constitutively active G protein α subunits in cancer cells

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Science Signaling  04 Sep 2018:
Vol. 11, Issue 546, eaao6852
DOI: 10.1126/scisignal.aao6852

Targeting mutant Gα

Activating mutations in G protein α subunits cause various diseases, including some forms of uveal melanoma (UM), an aggressive eye cancer. Onken et al. found that the plant-derived compound FR900359 blocked the growth of Gα-mutant UM cells in culture. FR900359 allosterically inhibited the guanine nucleotide exchange activity of constitutively active Gαq, thereby trapping it in inactive heterotrimers. The loss of Gαq signaling in UM cells induced redifferentiation and cell death. Targeting this compound, if safe, or synthetic derivatives to the uveal tumor tissue may be an effective treatment for patients.


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. We found that constitutively active Gαq in uveal melanoma (UM) cells was inhibited by the cyclic depsipeptide FR900359 (FR). FR allosterically inhibited guanosine diphosphate–for–guanosine triphosphate (GDP/GTP) exchange to trap constitutively active Gαq in inactive, GDP-bound Gαβγ heterotrimers. Allosteric inhibition of other Gα subunits was achieved by the introduction of an FR-binding site. In UM cells driven by constitutively active Gαq, FR inhibited second messenger signaling, arrested cell proliferation, reinstated melanocytic differentiation, and stimulated apoptosis. In contrast, FR had no effect on BRAF-driven UM cells. FR promoted UM cell differentiation by reactivating 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 (GPCRs) where targeting a single receptor is ineffective.

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