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BET bromodomain inhibitors synergize with ATR inhibitors in melanoma

Metastatic malignant melanoma continues to be a challenging disease despite clinical translation of the comprehensive understanding of driver mutations and how melanoma cells evade immune attack. In Myc-driven lymphoma, efficacy of epigenetic inhibitors of the bromodomain and extra-terminal domain (...

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Autores principales: Muralidharan, Somsundar Veppil, Einarsdottir, Berglind Osk, Bhadury, Joydeep, Lindberg, Mattias F, Wu, Jin, Campeau, Eric, Bagge, Roger Olofsson, Stierner, Ulrika, Ny, Lars, Nilsson, Lisa M, Nilsson, Jonas A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596569/
https://www.ncbi.nlm.nih.gov/pubmed/28796244
http://dx.doi.org/10.1038/cddis.2017.383
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author Muralidharan, Somsundar Veppil
Einarsdottir, Berglind Osk
Bhadury, Joydeep
Lindberg, Mattias F
Wu, Jin
Campeau, Eric
Bagge, Roger Olofsson
Stierner, Ulrika
Ny, Lars
Nilsson, Lisa M
Nilsson, Jonas A
author_facet Muralidharan, Somsundar Veppil
Einarsdottir, Berglind Osk
Bhadury, Joydeep
Lindberg, Mattias F
Wu, Jin
Campeau, Eric
Bagge, Roger Olofsson
Stierner, Ulrika
Ny, Lars
Nilsson, Lisa M
Nilsson, Jonas A
author_sort Muralidharan, Somsundar Veppil
collection PubMed
description Metastatic malignant melanoma continues to be a challenging disease despite clinical translation of the comprehensive understanding of driver mutations and how melanoma cells evade immune attack. In Myc-driven lymphoma, efficacy of epigenetic inhibitors of the bromodomain and extra-terminal domain (BET) family of bromodomain proteins can be enhanced by combination therapy with inhibitors of the DNA damage response kinase ATR. Whether this combination is active in solid malignancies like melanoma, and how it relates to immune therapy, has not previously investigated. To test efficacy and molecular consequences of combination therapies cultured melanoma cells were used. To assess tumor responses to therapies in vivo we use patient-derived xenografts and B6 mice transplanted with B16F10 melanoma cells. Concomitant inhibition of BET proteins and ATR of cultured melanoma cells resulted in similar effects as recently shown in lymphoma, such as induction of apoptosis and p62, implicated in autophagy, senescence-associated secretory pathway and ER stress. In vivo, apoptosis and suppression of subcutaneous growth of patient-derived melanoma and B16F10 cells were observed. Our data suggest that ATRI/BETI combination therapies are effective in melanoma.
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spelling pubmed-55965692017-09-14 BET bromodomain inhibitors synergize with ATR inhibitors in melanoma Muralidharan, Somsundar Veppil Einarsdottir, Berglind Osk Bhadury, Joydeep Lindberg, Mattias F Wu, Jin Campeau, Eric Bagge, Roger Olofsson Stierner, Ulrika Ny, Lars Nilsson, Lisa M Nilsson, Jonas A Cell Death Dis Original Article Metastatic malignant melanoma continues to be a challenging disease despite clinical translation of the comprehensive understanding of driver mutations and how melanoma cells evade immune attack. In Myc-driven lymphoma, efficacy of epigenetic inhibitors of the bromodomain and extra-terminal domain (BET) family of bromodomain proteins can be enhanced by combination therapy with inhibitors of the DNA damage response kinase ATR. Whether this combination is active in solid malignancies like melanoma, and how it relates to immune therapy, has not previously investigated. To test efficacy and molecular consequences of combination therapies cultured melanoma cells were used. To assess tumor responses to therapies in vivo we use patient-derived xenografts and B6 mice transplanted with B16F10 melanoma cells. Concomitant inhibition of BET proteins and ATR of cultured melanoma cells resulted in similar effects as recently shown in lymphoma, such as induction of apoptosis and p62, implicated in autophagy, senescence-associated secretory pathway and ER stress. In vivo, apoptosis and suppression of subcutaneous growth of patient-derived melanoma and B16F10 cells were observed. Our data suggest that ATRI/BETI combination therapies are effective in melanoma. Nature Publishing Group 2017-08 2017-08-10 /pmc/articles/PMC5596569/ /pubmed/28796244 http://dx.doi.org/10.1038/cddis.2017.383 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Muralidharan, Somsundar Veppil
Einarsdottir, Berglind Osk
Bhadury, Joydeep
Lindberg, Mattias F
Wu, Jin
Campeau, Eric
Bagge, Roger Olofsson
Stierner, Ulrika
Ny, Lars
Nilsson, Lisa M
Nilsson, Jonas A
BET bromodomain inhibitors synergize with ATR inhibitors in melanoma
title BET bromodomain inhibitors synergize with ATR inhibitors in melanoma
title_full BET bromodomain inhibitors synergize with ATR inhibitors in melanoma
title_fullStr BET bromodomain inhibitors synergize with ATR inhibitors in melanoma
title_full_unstemmed BET bromodomain inhibitors synergize with ATR inhibitors in melanoma
title_short BET bromodomain inhibitors synergize with ATR inhibitors in melanoma
title_sort bet bromodomain inhibitors synergize with atr inhibitors in melanoma
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596569/
https://www.ncbi.nlm.nih.gov/pubmed/28796244
http://dx.doi.org/10.1038/cddis.2017.383
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