Effects of oncogenic Gαq and Gα11 inhibition by FR900359 in uveal melanoma

Dominic Lapadula; Eduardo Farias; Clinita E. Randolph; Timothy J. Purwin; Dougan McGrath; Thomas H. Charpentier; Lihong Zhang; Shihua Wu; Mizue Terai; Takami Sato; Gregory G. Tall; Naiming Zhou; Philip B. Wedegaertner; Andrew E. Aplin; Julio Aguirre-Ghiso; Jeffrey L. Benovic

doi:10.1158/1541-7786.MCR-18-0574

Effects of oncogenic Gα_q and Gα₁₁ inhibition by FR900359 in uveal melanoma

Dominic Lapadula, Eduardo Farias, Clinita E. Randolph, Timothy J. Purwin, Dougan McGrath, Thomas H. Charpentier, Lihong Zhang, Shihua Wu, Mizue Terai, Takami Sato, Gregory G. Tall, Naiming Zhou, Philip B. Wedegaertner, Andrew E. Aplin, Julio Aguirre-Ghiso, Jeffrey L. Benovic

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

Abstract

Uveal melanoma is the most common intraocular tumor in adults and often metastasizes to the liver, leaving patients with few options. Recurrent activating mutations in the G proteins, Gaq and Ga11, are observed in approximately 93% of all uveal melanomas. Although therapeutic intervention of downstream Gaq/11 targets has been unsuccessful in treating uveal melanoma, we have found that the Gaq/11 inhibitor, FR900359 (FR), effectively inhibits oncogenic Gaq/11 signaling in uveal melanoma cells expressing either mutant Gaq or Ga11. Inhibition of oncogenic Gaq/11 by FR results in cell-cycle arrest and induction of apoptosis. Furthermore, colony formation is prevented by FR treatment of uveal melanoma cells in 3D-cell culture, providing promise for future in vivo studies. This suggests direct inhibition of activating Gaq/11 mutants may be a potential means of treating uveal melanoma. Implications: Oncogenic Gaq/11 inhibition by FR900359 may be a potential treatment option for those with uveal melanoma.

Original language	English (US)
Pages (from-to)	963-973
Number of pages	11
Journal	Molecular Cancer Research
Volume	17
Issue number	4
DOIs	https://doi.org/10.1158/1541-7786.MCR-18-0574
State	Published - 2019
Externally published	Yes

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1158/1541-7786.MCR-18-0574

Cite this

Lapadula, D., Farias, E., Randolph, C. E., Purwin, T. J., McGrath, D., Charpentier, T. H., Zhang, L., Wu, S., Terai, M., Sato, T., Tall, G. G., Zhou, N., Wedegaertner, P. B., Aplin, A. E., Aguirre-Ghiso, J., & Benovic, J. L. (2019). Effects of oncogenic Gα_q and Gα₁₁ inhibition by FR900359 in uveal melanoma. Molecular Cancer Research, 17(4), 963-973. https://doi.org/10.1158/1541-7786.MCR-18-0574

Lapadula, D, Farias, E, Randolph, CE, Purwin, TJ, McGrath, D, Charpentier, TH, Zhang, L, Wu, S, Terai, M, Sato, T, Tall, GG, Zhou, N, Wedegaertner, PB, Aplin, AE, Aguirre-Ghiso, J & Benovic, JL 2019, 'Effects of oncogenic Gα_q and Gα₁₁ inhibition by FR900359 in uveal melanoma', Molecular Cancer Research, vol. 17, no. 4, pp. 963-973. https://doi.org/10.1158/1541-7786.MCR-18-0574

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title = "Effects of oncogenic Gαq and Gα11 inhibition by FR900359 in uveal melanoma",

abstract = "Uveal melanoma is the most common intraocular tumor in adults and often metastasizes to the liver, leaving patients with few options. Recurrent activating mutations in the G proteins, Gaq and Ga11, are observed in approximately 93% of all uveal melanomas. Although therapeutic intervention of downstream Gaq/11 targets has been unsuccessful in treating uveal melanoma, we have found that the Gaq/11 inhibitor, FR900359 (FR), effectively inhibits oncogenic Gaq/11 signaling in uveal melanoma cells expressing either mutant Gaq or Ga11. Inhibition of oncogenic Gaq/11 by FR results in cell-cycle arrest and induction of apoptosis. Furthermore, colony formation is prevented by FR treatment of uveal melanoma cells in 3D-cell culture, providing promise for future in vivo studies. This suggests direct inhibition of activating Gaq/11 mutants may be a potential means of treating uveal melanoma. Implications: Oncogenic Gaq/11 inhibition by FR900359 may be a potential treatment option for those with uveal melanoma.",

author = "Dominic Lapadula and Eduardo Farias and Randolph, {Clinita E.} and Purwin, {Timothy J.} and Dougan McGrath and Charpentier, {Thomas H.} and Lihong Zhang and Shihua Wu and Mizue Terai and Takami Sato and Tall, {Gregory G.} and Naiming Zhou and Wedegaertner, {Philip B.} and Aplin, {Andrew E.} and Julio Aguirre-Ghiso and Benovic, {Jeffrey L.}",

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AU - Lapadula, Dominic

AU - Farias, Eduardo

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AU - Purwin, Timothy J.

AU - McGrath, Dougan

AU - Charpentier, Thomas H.

AU - Zhang, Lihong

AU - Wu, Shihua

AU - Terai, Mizue

AU - Sato, Takami

AU - Tall, Gregory G.

AU - Zhou, Naiming

AU - Wedegaertner, Philip B.

AU - Aplin, Andrew E.

AU - Aguirre-Ghiso, Julio

AU - Benovic, Jeffrey L.

PY - 2019

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N2 - Uveal melanoma is the most common intraocular tumor in adults and often metastasizes to the liver, leaving patients with few options. Recurrent activating mutations in the G proteins, Gaq and Ga11, are observed in approximately 93% of all uveal melanomas. Although therapeutic intervention of downstream Gaq/11 targets has been unsuccessful in treating uveal melanoma, we have found that the Gaq/11 inhibitor, FR900359 (FR), effectively inhibits oncogenic Gaq/11 signaling in uveal melanoma cells expressing either mutant Gaq or Ga11. Inhibition of oncogenic Gaq/11 by FR results in cell-cycle arrest and induction of apoptosis. Furthermore, colony formation is prevented by FR treatment of uveal melanoma cells in 3D-cell culture, providing promise for future in vivo studies. This suggests direct inhibition of activating Gaq/11 mutants may be a potential means of treating uveal melanoma. Implications: Oncogenic Gaq/11 inhibition by FR900359 may be a potential treatment option for those with uveal melanoma.

AB - Uveal melanoma is the most common intraocular tumor in adults and often metastasizes to the liver, leaving patients with few options. Recurrent activating mutations in the G proteins, Gaq and Ga11, are observed in approximately 93% of all uveal melanomas. Although therapeutic intervention of downstream Gaq/11 targets has been unsuccessful in treating uveal melanoma, we have found that the Gaq/11 inhibitor, FR900359 (FR), effectively inhibits oncogenic Gaq/11 signaling in uveal melanoma cells expressing either mutant Gaq or Ga11. Inhibition of oncogenic Gaq/11 by FR results in cell-cycle arrest and induction of apoptosis. Furthermore, colony formation is prevented by FR treatment of uveal melanoma cells in 3D-cell culture, providing promise for future in vivo studies. This suggests direct inhibition of activating Gaq/11 mutants may be a potential means of treating uveal melanoma. Implications: Oncogenic Gaq/11 inhibition by FR900359 may be a potential treatment option for those with uveal melanoma.

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