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 mutations of the GNAQ gene: a frequent event in primary melanocytic neoplasms of the central nervous system.Acta Neuropathol. 2010; 119: 317-323Crossref PubMed Scopus (81) Google Scholar, 5Sheng X. Kong Y. Li Y. Zhang Q. Si L. Cui C. Chi Z. Tang B. Mao L. Lian B. Wang X. Yan X. Li S. Dai J. Guo J. GNAQ and GNA11 mutations occur in 9.5% of mucosal melanoma and are associated with poor prognosis.Eur. J. Cancer. 2016; 65: 156-163Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 6Joseph N.M. Brunt E.M. Marginean C. Nalbantoglu Ilk. Snover D.C. Thung S.N. Yeh M.M. Umetsu S.E. Ferrell L.D. Gill R.M. Frequent GNAQ and GNA14 mutations in hepatic small vessel neoplasm.Am. J. Surg. Pathol. 2018; 42: 1201-1207Crossref PubMed Scopus (24) Google Scholar, 7Shirley M.D. Tang H. Gallione C.J. Baugher J.D. Frelin L.P. Cohen B. North P.E. Marchuk D.A. Comi A.M. Pevsner J. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ.N. Engl. J. Med. 2013; 368: 1971-1979Crossref PubMed Scopus (518) Google Scholar, 8Bichsel C.A. Goss J. Alomari M. Alexandrescu S. Robb R. Smith L.E. Hochman M. Greene A. Bischoff J. Association of somatic GNAQ mutation with Capillary Malformations in a case of choroidal hemangioma.JAMA Ophthalmol. 2019; 137: 91-95Crossref PubMed Scopus (11) Google Scholar, 9Nesbit M.A. Hannan F.M. Howles S.A. Babinsky V.N. Head R.A. Cranston T. Rust N. Hobbs M.R. Heath H. Thakker R.V. Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia.N. Engl. J. Med. 2013; 368: 2476-2486Crossref PubMed Scopus (234) Google Scholar, 10Li C. H. M.A. caused by mutation in and PubMed Scopus Google Scholar, T. H. R. G. S. C. GNAQ mutations in and choroidal 2019; Full Text Full Text PDF PubMed Scopus Google UM is because patients with metastatic disease often succumb within months of effective therapy N. Uveal and of primary Ophthalmol. PubMed Scopus Google of metastatic UM have of or inhibitors of oncogenic proteins and T. B. disease from uveal and J. Ophthalmol. PubMed Scopus Google therapeutic for metastatic UM are that mutant constitutively active Gq/11 be targeted in UM and other diseases E.M. S. Gq proteins therapeutic Full Text Full Text PDF PubMed Scopus Google Oncogenic Gq/11 α-subunits are constitutively active in the for G oncogenic Gq/11 can be inhibited by FR900359 (FR) or M. S. Y. of a from Scopus Google Scholar, R. S. S. T. A. Y. S. N. M. M. N. et of FR900359 PubMed Scopus Google Scholar, M.D. Wang S. constitutively active G a in 2018; PubMed Scopus Google Scholar, Zhang L. S. M. T. N. J. et of oncogenic and by FR900359 in uveal 2019; PubMed Scopus Google Scholar, S. X. N. J. E.M. A. T. R. S. S. R. et of and in 2019; PubMed Scopus Google Scholar, X. N. D.C. H. Wang Z. S. A. M. P. Q. et of that the GNAQ uveal melanoma the 2019; Full Text Full Text PDF PubMed Scopus Google a of that by the Gq/11/14 subfamily R. S. S. T. A. Y. S. N. M. M. N. et of FR900359 PubMed Scopus Google Scholar, J. T. M. T. Y. M. A novel Full Text Full Text PDF PubMed Scopus Google is occur because oncogenic Gq/11 α-subunits can or FR and M.D. Wang S. constitutively active G a in 2018; PubMed Scopus Google by E.M. S. Gq proteins therapeutic Full Text Full Text PDF PubMed Scopus Google Scholar, R. S. S. T. A. Y. S. N. M. M. N. et of FR900359 PubMed Scopus Google Scholar) and oncogenic M.D. Wang S. constitutively active G a in 2018; PubMed Scopus Google Scholar, Zhang L. S. M. T. N. J. et of oncogenic and by FR900359 in uveal 2019; PubMed Scopus Google Scholar, S. X. N. J. E.M. A. T. R. S. S. R. et of and in 2019; PubMed Scopus Google Scholar, X. N. D.C. H. Wang Z. S. A. M. P. Q. et of that the GNAQ uveal melanoma the 2019; Full Text Full Text PDF PubMed Scopus Google UM cell lines driven by oncogenic Gq/11 the cell and can apoptosis redifferentiation cells M.D. Wang S. constitutively active G a in 2018; PubMed Scopus Google Scholar, Zhang L. S. M. T. N. J. et of oncogenic and by FR900359 in uveal 2019; PubMed Scopus Google Scholar, S. X. N. J. E.M. A. T. R. S. S. R. et of and in 2019; PubMed Scopus Google Scholar, X. N. D.C. H. Wang Z. S. A. M. P. Q. et of that the GNAQ uveal melanoma the 2019; Full Text Full Text PDF PubMed Scopus Google UM cell which are M.D. Wang S. constitutively active G a in 2018; PubMed Scopus Google Scholar, Zhang L. S. M. T. N. J. et of oncogenic and by FR900359 in uveal 2019; PubMed Scopus Google Scholar, S. X. N. J. E.M. A. T. R. S. S. R. et of and in 2019; PubMed Scopus Google Scholar, X. N. D.C. H. Wang Z. S. A. M. P. Q. et of that the GNAQ uveal melanoma the 2019; Full Text Full Text PDF PubMed Scopus Google therapeutic potential of in UM is and be because not and oncogenic Gq/11 E.M. S. Gq proteins therapeutic Full Text Full Text PDF PubMed Scopus Google and J. T. M. T. Y. M. A novel Full Text Full Text PDF PubMed Scopus Google Scholar, T. M. Y. T. T. H. J. T. of YM-254890, a and in PubMed Scopus Google Scholar, M. R. A. A. R. M. S. of Gq in mouse models of Med. PubMed Scopus Google Scholar, M.M. J. S.A. I. M. S. P. of for G class G 2019; PubMed Scopus Google Scholar) for and Li R. J. Wang S. M. J.M. S. N. is for and PubMed Scopus Google Scholar, D.A. N. A. S. in and PubMed Scopus Google Scholar, M.A. M.A. of in the PubMed Scopus Google Scholar, N. H. A. J. S. of pressure induced of in Med. PubMed Scopus Google administered systemically that Gq/11 in is be suggested by of Gq/11 S. L.P. A. I. and in J. PubMed Scopus Google strongly oncogenic Gq/11 in UM tumors be inhibited for therapeutic have that can growth of UM tumors in mouse xenograft models S. X. N. J. E.M. A. T. R. S. S. R. et of and in 2019; PubMed Scopus Google Scholar, G. C. R. Wang N. M.R. Y. J. et of and therapeutic in uveal PubMed Google are can primary metastatic UM tumor cells from is by the of oncogenic Gq/11 tumor class or metastatic or of UM tumor has or Here, we have addressed all of constitutively active Gq/11 mutants have been in UM 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, B. A. N. S. X. A.M. et and of uveal PubMed Scopus Google Scholar, J. C. J. J.M. V. V. L. M. Tang M. A. et and in uveal Full Text Full Text PDF PubMed Scopus Google been and be inhibited by FR or M.D. Wang S. constitutively active G a in 2018; PubMed Scopus Google Scholar, Zhang L. S. M. T. N. J. et of oncogenic and by FR900359 in uveal 2019; PubMed Scopus Google Scholar, S. X. N. J. E.M. A. T. R. S. S. R. et of and in 2019; PubMed Scopus Google Scholar, X. N. D.C. H. Wang Z. S. A. M. P. Q. et of that the GNAQ uveal melanoma the 2019; Full Text Full Text PDF PubMed Scopus Google we of Gq/11 mutants that UM with a Gq/11-driven in a common that affect the We found that mutant G induced and inhibited by FR with and we found that UM cell lines driven by oncogenic Gq/11 mutants FR in or FR inhibited growth of all Gq/11-driven UM cell but with by FR arrested the cell of all Gq/11-driven UM cell indicated by of and cells and induced apoptosis only in of and indicated by of cells with and FR did not affect or of a UM cell M.D. Wang S. constitutively active G a in 2018; PubMed Scopus Google Scholar, Zhang L. S. M. T. N. J. et of oncogenic and by FR900359 in uveal 2019; PubMed Scopus Google Scholar, S. X. N. J. E.M. A. T. R. S. S. R. et of and in 2019; PubMed Scopus Google the of FR for oncogenic Gq/11 in UM. 1 and class 2 primary UM tumors have low and high of M.D. Worley L.A. Harbour J.W. in uveal melanoma and metastatic PubMed Scopus Google Scholar, M.D. Worley L.A. M.M. T. et of a in uveal 119: Full Text Full Text PDF PubMed Scopus Google 1 UM tumors the that by 2 UM tumors are J.W. M.D. Duan S. L. Worley L.A. Council M.L. C. Bowcock A.M. Frequent mutation of in uveal 2010; PubMed Scopus Google Scholar) and J. C. J. J.M. V. V. L. M. Tang M. A. et and in uveal Full Text Full Text PDF PubMed Scopus Google all UM cell lines are from class 1 tumors K.G. X. J. Sozen M.M. C. S. Bastian B.C. S.E. and of uveal melanoma cell PubMed Scopus Google the of of primary UM tumor cells can be targeted by We addressed by (class and (class cell which from of primary UM tumors N. A. A. G. J. L. N. S. P. X. 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Activating mutations of the GNAQ gene: a frequent event in primary melanocytic neoplasms of the central nervous system.Acta Neuropathol. 2010; 119: 317-323Crossref PubMed Scopus (81) Google mucosal melanoma X. Kong Y. Li Y. Zhang Q. Si L. Cui C. Chi Z. Tang B. Mao L. Lian B. Wang X. Yan X. Li S. Dai J. Guo J. GNAQ and GNA11 mutations occur in 9.5% of mucosal melanoma and are associated with poor prognosis.Eur. J. Cancer. 2016; 65: 156-163Abstract Full Text Full Text PDF PubMed Scopus (40) Google choroidal C.A. Goss J. Alomari M. Alexandrescu S. Robb R. Smith L.E. Hochman M. Greene A. Bischoff J. Association of somatic GNAQ mutation with Capillary Malformations in a case of choroidal hemangioma.JAMA Ophthalmol. 2019; 137: 91-95Crossref PubMed Scopus (11) Google Scholar, T. H. R. G. S. C. GNAQ mutations in and choroidal 2019; Full Text Full Text PDF PubMed Scopus Google and hepatic small vessel neoplasms N.M. Brunt E.M. Marginean C. Nalbantoglu Ilk. Snover D.C. Thung S.N. Yeh M.M. Umetsu S.E. Ferrell L.D. Gill R.M. Frequent GNAQ and GNA14 mutations in hepatic small vessel neoplasm.Am. J. Surg. Pathol. 2018; 42: 1201-1207Crossref PubMed Scopus (24) Google in syndrome M.D. Tang H. Gallione C.J. Baugher J.D. Frelin L.P. Cohen B. North P.E. Marchuk D.A. Comi A.M. Pevsner J. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ.N. Engl. J. Med. 2013; 368: 1971-1979Crossref PubMed Scopus (518) Google forms of hypercalcemia and M.A. Hannan F.M. Howles S.A. Babinsky V.N. Head R.A. Cranston T. Rust N. Hobbs M.R. Heath H. Thakker R.V. Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia.N. Engl. J. Med. 2013; 368: 2476-2486Crossref PubMed Scopus (234) Google and C. H. M.A. caused by mutation in and PubMed Scopus Google for all of potentially be by novel therapeutic FR900359 (FR) from R. S. S. T. A. Y. S. N. M. M. N. et of FR900359 PubMed Scopus Google a driven by the and Wang Q. 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