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Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma

The discovery of activating BRAF mutations in approximately 50% of melanomas has led to the development of MAPK pathway inhibitors, which have transformed melanoma therapy. However, not all BRAF-V600E melanomas respond to MAPK inhibition. Therefore, it is important to understand why tumors with the...

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Autores principales: Krepler, Clemens, Xiao, Min, Samanta, Minu, Vultur, Adina, Chen, Hsin-Yi, Brafford, Patricia, Reyes-Uribe, Patricia I., Halloran, Molly, Chen, Thomas, He, Xu, Hristova, Denitsa, Liu, Qin, Samatar, Ahmed A., Davies, Michael A., Nathanson, Katherine L., Fukunaga-Kalabis, Mizuho, Herlyn, Meenhard, Villanueva, Jessie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342073/
https://www.ncbi.nlm.nih.gov/pubmed/27655717
http://dx.doi.org/10.18632/oncotarget.12078
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author Krepler, Clemens
Xiao, Min
Samanta, Minu
Vultur, Adina
Chen, Hsin-Yi
Brafford, Patricia
Reyes-Uribe, Patricia I.
Halloran, Molly
Chen, Thomas
He, Xu
Hristova, Denitsa
Liu, Qin
Samatar, Ahmed A.
Davies, Michael A.
Nathanson, Katherine L.
Fukunaga-Kalabis, Mizuho
Herlyn, Meenhard
Villanueva, Jessie
author_facet Krepler, Clemens
Xiao, Min
Samanta, Minu
Vultur, Adina
Chen, Hsin-Yi
Brafford, Patricia
Reyes-Uribe, Patricia I.
Halloran, Molly
Chen, Thomas
He, Xu
Hristova, Denitsa
Liu, Qin
Samatar, Ahmed A.
Davies, Michael A.
Nathanson, Katherine L.
Fukunaga-Kalabis, Mizuho
Herlyn, Meenhard
Villanueva, Jessie
author_sort Krepler, Clemens
collection PubMed
description The discovery of activating BRAF mutations in approximately 50% of melanomas has led to the development of MAPK pathway inhibitors, which have transformed melanoma therapy. However, not all BRAF-V600E melanomas respond to MAPK inhibition. Therefore, it is important to understand why tumors with the same oncogenic driver have variable responses to MAPK inhibitors. Here, we show that concurrent loss of PTEN and activation of the Notch pathway is associated with poor response to the ERK inhibitor SCH772984, and that co-inhibition of Notch and ERK decreased viability in BRAF-V600E melanomas. Additionally, patients with low PTEN and Notch activation had significantly shorter progression free survival when treated with BRAF inhibitors. Our studies provide a rationale to further develop combination strategies with Notch antagonists to maximize the efficacy of MAPK inhibition in melanoma. Our findings should prompt the evaluation of combinations co-targeting MAPK/ERK and Notch as a strategy to improve current therapies and warrant further evaluation of co-occurrence of aberrant PTEN and Notch activation as predictive markers of response to therapy.
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spelling pubmed-53420732017-03-24 Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma Krepler, Clemens Xiao, Min Samanta, Minu Vultur, Adina Chen, Hsin-Yi Brafford, Patricia Reyes-Uribe, Patricia I. Halloran, Molly Chen, Thomas He, Xu Hristova, Denitsa Liu, Qin Samatar, Ahmed A. Davies, Michael A. Nathanson, Katherine L. Fukunaga-Kalabis, Mizuho Herlyn, Meenhard Villanueva, Jessie Oncotarget Research Paper The discovery of activating BRAF mutations in approximately 50% of melanomas has led to the development of MAPK pathway inhibitors, which have transformed melanoma therapy. However, not all BRAF-V600E melanomas respond to MAPK inhibition. Therefore, it is important to understand why tumors with the same oncogenic driver have variable responses to MAPK inhibitors. Here, we show that concurrent loss of PTEN and activation of the Notch pathway is associated with poor response to the ERK inhibitor SCH772984, and that co-inhibition of Notch and ERK decreased viability in BRAF-V600E melanomas. Additionally, patients with low PTEN and Notch activation had significantly shorter progression free survival when treated with BRAF inhibitors. Our studies provide a rationale to further develop combination strategies with Notch antagonists to maximize the efficacy of MAPK inhibition in melanoma. Our findings should prompt the evaluation of combinations co-targeting MAPK/ERK and Notch as a strategy to improve current therapies and warrant further evaluation of co-occurrence of aberrant PTEN and Notch activation as predictive markers of response to therapy. Impact Journals LLC 2016-09-16 /pmc/articles/PMC5342073/ /pubmed/27655717 http://dx.doi.org/10.18632/oncotarget.12078 Text en Copyright: © 2016 Krepler et al. http://creativecommons.org/licenses/by/3.0/ 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 credited.
spellingShingle Research Paper
Krepler, Clemens
Xiao, Min
Samanta, Minu
Vultur, Adina
Chen, Hsin-Yi
Brafford, Patricia
Reyes-Uribe, Patricia I.
Halloran, Molly
Chen, Thomas
He, Xu
Hristova, Denitsa
Liu, Qin
Samatar, Ahmed A.
Davies, Michael A.
Nathanson, Katherine L.
Fukunaga-Kalabis, Mizuho
Herlyn, Meenhard
Villanueva, Jessie
Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma
title Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma
title_full Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma
title_fullStr Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma
title_full_unstemmed Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma
title_short Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma
title_sort targeting notch enhances the efficacy of erk inhibitors in braf-v600e melanoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342073/
https://www.ncbi.nlm.nih.gov/pubmed/27655717
http://dx.doi.org/10.18632/oncotarget.12078
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