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Impact of Combined mTOR and MEK Inhibition in Uveal Melanoma Is Driven by Tumor Genotype

Uveal melanomas possess activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) pathways. MAPK activation occurs via somatic mutations in the heterotrimeric G protein subunits GNAQ and GNA11 for over 70% of tumors and le...

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Autores principales: Ho, Alan L., Musi, Elgilda, Ambrosini, Grazia, Nair, Jayasree S., Deraje Vasudeva, Shyamprasad, de Stanchina, Elisa, Schwartz, Gary K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393714/
https://www.ncbi.nlm.nih.gov/pubmed/22808163
http://dx.doi.org/10.1371/journal.pone.0040439
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author Ho, Alan L.
Musi, Elgilda
Ambrosini, Grazia
Nair, Jayasree S.
Deraje Vasudeva, Shyamprasad
de Stanchina, Elisa
Schwartz, Gary K.
author_facet Ho, Alan L.
Musi, Elgilda
Ambrosini, Grazia
Nair, Jayasree S.
Deraje Vasudeva, Shyamprasad
de Stanchina, Elisa
Schwartz, Gary K.
author_sort Ho, Alan L.
collection PubMed
description Uveal melanomas possess activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) pathways. MAPK activation occurs via somatic mutations in the heterotrimeric G protein subunits GNAQ and GNA11 for over 70% of tumors and less frequently via V600E BRAF mutations. In this report, we describe the impact of dual pathway inhibition upon uveal melanoma cell lines with the MEK inhibitor selumetinib (AZD6244/ARRY-142886) and the ATP-competitive mTOR kinase inhibitor AZD8055. While synergistic reductions in cell viability were observed with AZD8055/selumetinib in both BRAF and GNAQ mutant cell lines, apoptosis was preferentially induced in BRAF mutant cells only. In vitro apoptosis assay results were predictive of in vivo drug efficacy as tumor regressions were observed only in a BRAF mutant xenograft model, but not GNAQ mutant model. We went on to discover that GNAQ promotes relative resistance to AZD8055/selumetinib-induced apoptosis in GNAQ mutant cells. For BRAF mutant cells, both AKT and 4E-BP1 phosphorylation were modulated by the combination; however, decreasing AKT phosphorylation alone was not sufficient and decreasing 4E-BP1 phosphorylation was not required for apoptosis. Instead, cooperative mTOR complex 2 (mTORC2) and MEK inhibition resulting in downregulation of the pro-survival protein MCL-1 was found to be critical for combination-induced apoptosis. These results suggest that the clinical efficacy of combined MEK and mTOR kinase inhibition will be determined by tumor genotype, and that BRAF mutant malignancies will be particularly susceptible to this strategy.
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spelling pubmed-33937142012-07-17 Impact of Combined mTOR and MEK Inhibition in Uveal Melanoma Is Driven by Tumor Genotype Ho, Alan L. Musi, Elgilda Ambrosini, Grazia Nair, Jayasree S. Deraje Vasudeva, Shyamprasad de Stanchina, Elisa Schwartz, Gary K. PLoS One Research Article Uveal melanomas possess activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) pathways. MAPK activation occurs via somatic mutations in the heterotrimeric G protein subunits GNAQ and GNA11 for over 70% of tumors and less frequently via V600E BRAF mutations. In this report, we describe the impact of dual pathway inhibition upon uveal melanoma cell lines with the MEK inhibitor selumetinib (AZD6244/ARRY-142886) and the ATP-competitive mTOR kinase inhibitor AZD8055. While synergistic reductions in cell viability were observed with AZD8055/selumetinib in both BRAF and GNAQ mutant cell lines, apoptosis was preferentially induced in BRAF mutant cells only. In vitro apoptosis assay results were predictive of in vivo drug efficacy as tumor regressions were observed only in a BRAF mutant xenograft model, but not GNAQ mutant model. We went on to discover that GNAQ promotes relative resistance to AZD8055/selumetinib-induced apoptosis in GNAQ mutant cells. For BRAF mutant cells, both AKT and 4E-BP1 phosphorylation were modulated by the combination; however, decreasing AKT phosphorylation alone was not sufficient and decreasing 4E-BP1 phosphorylation was not required for apoptosis. Instead, cooperative mTOR complex 2 (mTORC2) and MEK inhibition resulting in downregulation of the pro-survival protein MCL-1 was found to be critical for combination-induced apoptosis. These results suggest that the clinical efficacy of combined MEK and mTOR kinase inhibition will be determined by tumor genotype, and that BRAF mutant malignancies will be particularly susceptible to this strategy. Public Library of Science 2012-07-10 /pmc/articles/PMC3393714/ /pubmed/22808163 http://dx.doi.org/10.1371/journal.pone.0040439 Text en Ho et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Ho, Alan L.
Musi, Elgilda
Ambrosini, Grazia
Nair, Jayasree S.
Deraje Vasudeva, Shyamprasad
de Stanchina, Elisa
Schwartz, Gary K.
Impact of Combined mTOR and MEK Inhibition in Uveal Melanoma Is Driven by Tumor Genotype
title Impact of Combined mTOR and MEK Inhibition in Uveal Melanoma Is Driven by Tumor Genotype
title_full Impact of Combined mTOR and MEK Inhibition in Uveal Melanoma Is Driven by Tumor Genotype
title_fullStr Impact of Combined mTOR and MEK Inhibition in Uveal Melanoma Is Driven by Tumor Genotype
title_full_unstemmed Impact of Combined mTOR and MEK Inhibition in Uveal Melanoma Is Driven by Tumor Genotype
title_short Impact of Combined mTOR and MEK Inhibition in Uveal Melanoma Is Driven by Tumor Genotype
title_sort impact of combined mtor and mek inhibition in uveal melanoma is driven by tumor genotype
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393714/
https://www.ncbi.nlm.nih.gov/pubmed/22808163
http://dx.doi.org/10.1371/journal.pone.0040439
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