The phosphoinositide 3-kinase a selective inhibitor BYL719 enhances the effect of the protein kinase C inhibitor AEB071 in GNAQ/GNA11-mutant uveal melanoma cells Journal Article

   

Authors:	Musi, E.; Ambrosini, G.; de Stanchina, E.; Schwartz, G. K.
Article Title:	The phosphoinositide 3-kinase a selective inhibitor BYL719 enhances the effect of the protein kinase C inhibitor AEB071 in GNAQ/GNA11-mutant uveal melanoma cells
Abstract:	G-protein mutations are one of the most common mutations occurring in uveal melanoma activating the protein kinase C (PKC)/mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K)/AKT pathways. In this study, we described the effect of dual pathway inhibition in uveal melanoma harboring GNAQandGNA11 mutations via PKCinhibition withAEB071 (sotrastaurin) and PI3K/AKT inhibition with BYL719, a selective PI3Ka inhibitor. Growth inhibition was observed in GNAQ/GNA11-mutant cells with AEB071 versus no activity in wild-type cells. In theGNAQ-mutant cells,AEB071 decreased phosphorylation of myristoylated alanine-rich C-kinase substrate, a substrate of PKC, along with ERK1/2 and ribosomal S6, but persistent AKT activation was present. BYL719 had minimal antiproliferative activity in all uveal melanoma cell lines, and inhibited phosphorylation ofAKT in most cell lines. In theGNA11-mutant cell line, similar effects were observed with ERK1/2 inhibition, mostly inhibited by BYL719. With the combination treatment, both GNAQ- and GNA11-mutant cell lines showed synergistic inhibition of cell proliferation and apoptotic cell death. In vivo studies correlated with in vitro findings showing reduced xenograft tumor growth with the combination therapy in a GNAQ-mutant model. These findings suggest a new therapy treatment option for G-protein-mutant uveal melanoma with a focus on specific targeting of multiple downstream pathways as part of combination therapy. © 2014 American Association for Cancer Research.
Journal Title:	Molecular Cancer Therapeutics
Volume:	13
Issue:	5
ISSN:	1535-7163
Publisher:	American Association for Cancer Research
Date Published:	2014-05-01
Start Page:	1044
End Page:	1053
Language:	English
DOI:	10.1158/1535-7163.mct-13-0550
PROVIDER:	scopus
PUBMED:	24563540
PMCID:	PMC4146424
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84899863027&partnerID=40&md5=5328090a0b75c3c0bd13e5b0810162fb
Notes:	Mol. Cancer Ther. -- Export Date: 2 June 2014 -- CODEN: MCTOC -- Source: Scopus