title: The phosphoinositide 3-kinase α 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 GNAQ and GNA11 mutations via PKC inhibition with AEB071 (sotrastaurin) and PI3K/AKT inhibition with BYL719, a selective PI3Kα inhibitor. Growth inhibition was observed in GNAQ/GNA11-mutant cells with AEB071 versus no activity in wild-type cells. In the GNAQ-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 of AKT in most cell lines. In the GNA11-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.
authors.affiliation: Authors' Affiliation: Jennifer Goodman Linn Laboratory of New Drug Development in Sarcoma and Rare Cancers, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Elgilda
authors.initials: E
authors.lastname: Musi
authors.forename: Grazia
authors.initials: G
authors.lastname: Ambrosini
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020868:Gene Silencing; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden; D014604:Uveal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000098943:Uveal Melanoma
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D044385:GTP-Binding Protein alpha Subunits; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D011758:Pyrroles; D011799:Quinazolines; D013844:Thiazoles; C554062:GNA11 protein, human; C554061:GNAQ protein, human; C585539:Alpelisib; C543528:sotrastaurin; C484760:PIK3CA protein, human