TY - JOUR
T1 - Effects of oncogenic Gαq and Gα11 inhibition by FR900359 in uveal melanoma
AU - Lapadula, Dominic
AU - Farias, Eduardo
AU - Randolph, Clinita E.
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.
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
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.
UR - http://www.scopus.com/inward/record.url?scp=85064067664&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-18-0574
DO - 10.1158/1541-7786.MCR-18-0574
M3 - Article
C2 - 30567972
AN - SCOPUS:85064067664
SN - 1541-7786
VL - 17
SP - 963
EP - 973
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 4
ER -