Targeting primary and metastatic uveal melanoma with a G protein inhibitor

J Biol Chem. 2021 Jan-Jun;296:100403. doi: 10.1016/j.jbc.2021.100403. Epub 2021 Feb 10.


Uveal melanoma (UM) is the most common intraocular tumor in adults. Nearly half of UM patients develop metastatic disease and often succumb within months because effective therapy is lacking. A novel therapeutic approach has been suggested by the discovery that UM cell lines driven by mutant constitutively active Gq or G11 can be targeted by FR900359 (FR) or YM-254890, which are bioavailable, selective inhibitors of the Gq/11/14 subfamily of heterotrimeric G proteins. Here, we have addressed the therapeutic potential of FR for UM. We found that FR inhibited all oncogenic Gq/11 mutants reported in UM. FR arrested growth of all Gq/11-driven UM cell lines tested, but induced apoptosis only in a few. Similarly, FR inhibited growth of, but did not efficiently kill, UM tumor cells from biopsies of primary or metastatic tumors. FR evoked melanocytic redifferentiation of UM tumor cells with low (class 1), but not high (class 2), metastatic potential. FR administered systemically below its LD50 strongly inhibited growth of PDX-derived class 1 and class 2 UM tumors in mouse xenograft models and reduced blood pressure transiently. FR did not regress xenografted UM tumors or significantly affect heart rate, liver function, hematopoiesis, or behavior. These results indicated the existence of a therapeutic window in which FR can be explored for treating UM and potentially other diseases caused by constitutively active Gq/11.

Keywords: G protein inhibitor; G proteins/heterotrimeric; anticancer drug; drug action; eye; melanoma; uveal melanoma.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Depsipeptides / pharmacology*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / antagonists & inhibitors*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / secondary
  • Male
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / metabolism
  • Melanoma / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mutation
  • Neoplasm Metastasis
  • Peptides, Cyclic / pharmacology*
  • Uveal Neoplasms / drug therapy*
  • Uveal Neoplasms / genetics
  • Uveal Neoplasms / metabolism
  • Uveal Neoplasms / pathology
  • Xenograft Model Antitumor Assays


  • Depsipeptides
  • FR900359
  • Peptides, Cyclic
  • YM-254890
  • GTP-Binding Protein alpha Subunits, Gq-G11

Supplementary concepts

  • Uveal melanoma