{"doi":"10.1016/j.jbc.2021.100403","title":"Targeting primary and metastatic uveal melanoma with a G protein inhibitor","abstract":"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. 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. Mutant constitutively active forms of Gq or G11 (Gq/11) α-subunits of heterotrimeric G proteins cause uveal melanoma (UM) (1Van Raamsdonk C.D. Bezrookove V. Green G. Bauer J. Gaugler L. O’Brien J.M. Simpson E.M. Barsh G.S. Bastian B.C. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi.Nature. 2009; 457: 599-602Crossref PubMed Scopus (999) Google Scholar, 2Van Raamsdonk C.D. Griewank K.G. Crosby M.B. Garrido M.C. Vemula S. Wiesner T. Obenauf A.C. Wackernagel W. Green G. Bouvier N. Sozen M.M. Baimukanova G. Roy R. Heguy A. Dolgalev I. et al.Mutations in GNA11 in uveal melanoma.N. Engl. J. Med. 2010; 363: 2191-2199Crossref PubMed Scopus (926) Google Scholar, 3Onken M.D. Worley L.A. Long M.D. Duan S. Council M.L. Bowcock A.M. Harbour J.W. Oncogenic mutations in GNAQ occur early in uveal melanoma.Investig. Ophthalmol. Vis. Sci. 2008; 49: 5230-5234Crossref PubMed Scopus (233) Google Scholar) and several other diseases and disorders (4Küsters-Vandevelde H.V.N. Klaasen A. Küsters B. Groenen P.J.T.A. Van Engen-Van Grunsven I.A.C.H. Van Dijk M.R.C.F. Reifenberger G. Wesseling P. Blokx W.A.M. Activating mu","journal":"Journal of Biological Chemistry","year":2021,"id":162826,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":44,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":681273,"name":"Carol M. Makepeace","orcid":null,"position":1,"is_corresponding":false},{"id":680639,"name":"Kevin M. Kaltenbronn","orcid":"0000-0001-8331-5718","position":2,"is_corresponding":false},{"id":680640,"name":"Joelle Choi","orcid":"0000-0002-8633-7733","position":3,"is_corresponding":false},{"id":290805,"name":"Leonel F. Hernandez‐Aya","orcid":"0000-0002-0684-8120","position":4,"is_corresponding":false},{"id":464206,"name":"Katherine N. Weilbaecher","orcid":"0000-0002-7137-4742","position":5,"is_corresponding":false},{"id":533628,"name":"Kisha Piggott","orcid":"0000-0002-6276-8694","position":6,"is_corresponding":false},{"id":533629,"name":"P. Kumar Rao","orcid":"0000-0002-8445-7897","position":7,"is_corresponding":false},{"id":225564,"name":"Carla M. Yuede","orcid":"0000-0001-6362-4767","position":8,"is_corresponding":false},{"id":680641,"name":"Alethia J Dixon","orcid":"0000-0002-4374-0688","position":9,"is_corresponding":false},{"id":329350,"name":"Patrick Osei‐Owusu","orcid":"0000-0002-4581-7044","position":10,"is_corresponding":false},{"id":202584,"name":"John A. Cooper","orcid":"0000-0002-0933-4571","position":11,"is_corresponding":false},{"id":329352,"name":"Kendall Blumer","orcid":"0000-0002-5743-6206","position":12,"is_corresponding":false},{"id":331305,"name":"Michael D. Onken","orcid":"0000-0003-4082-1105","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-18T23:45:05.641178Z","pmid":"33577798","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}