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Efficacy of ATR inhibitors as single agents in Ewing sarcoma

Ewing sarcomas (ES) are pediatric bone tumors that arise from a driver translocation, most frequently EWS/FLI1. Current ES treatment involves DNA damaging agents, yet the basis for the sensitivity to these therapies remains unknown. Oncogene-induced replication stress (RS) is a known source of endog...

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Autores principales: Nieto-Soler, Maria, Morgado-Palacin, Isabel, Lafarga, Vanesa, Lecona, Emilio, Murga, Matilde, Callen, Elsa, Azorin, Daniel, Alonso, Javier, Lopez, Andres J., Nussenzweig, Andre, Fernandez-Capetillo, Oscar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312273/
https://www.ncbi.nlm.nih.gov/pubmed/27577084
http://dx.doi.org/10.18632/oncotarget.11643
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author Nieto-Soler, Maria
Morgado-Palacin, Isabel
Lafarga, Vanesa
Lecona, Emilio
Murga, Matilde
Callen, Elsa
Azorin, Daniel
Alonso, Javier
Lopez, Andres J.
Nussenzweig, Andre
Fernandez-Capetillo, Oscar
author_facet Nieto-Soler, Maria
Morgado-Palacin, Isabel
Lafarga, Vanesa
Lecona, Emilio
Murga, Matilde
Callen, Elsa
Azorin, Daniel
Alonso, Javier
Lopez, Andres J.
Nussenzweig, Andre
Fernandez-Capetillo, Oscar
author_sort Nieto-Soler, Maria
collection PubMed
description Ewing sarcomas (ES) are pediatric bone tumors that arise from a driver translocation, most frequently EWS/FLI1. Current ES treatment involves DNA damaging agents, yet the basis for the sensitivity to these therapies remains unknown. Oncogene-induced replication stress (RS) is a known source of endogenous DNA damage in cancer, which is suppressed by ATR and CHK1 kinases. We here show that ES suffer from high endogenous levels of RS, rendering them particularly dependent on the ATR pathway. Accordingly, two independent ATR inhibitors show in vitro toxicity in ES cell lines as well as in vivo efficacy in ES xenografts as single agents. Expression of EWS/FLI1 or EWS/ERG oncogenic translocations sensitizes non-ES cells to ATR inhibitors. Our data shed light onto the sensitivity of ES to genotoxic agents, and identify ATR inhibitors as a potential therapy for Ewing Sarcomas.
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spelling pubmed-53122732017-03-06 Efficacy of ATR inhibitors as single agents in Ewing sarcoma Nieto-Soler, Maria Morgado-Palacin, Isabel Lafarga, Vanesa Lecona, Emilio Murga, Matilde Callen, Elsa Azorin, Daniel Alonso, Javier Lopez, Andres J. Nussenzweig, Andre Fernandez-Capetillo, Oscar Oncotarget Priority Research Paper Ewing sarcomas (ES) are pediatric bone tumors that arise from a driver translocation, most frequently EWS/FLI1. Current ES treatment involves DNA damaging agents, yet the basis for the sensitivity to these therapies remains unknown. Oncogene-induced replication stress (RS) is a known source of endogenous DNA damage in cancer, which is suppressed by ATR and CHK1 kinases. We here show that ES suffer from high endogenous levels of RS, rendering them particularly dependent on the ATR pathway. Accordingly, two independent ATR inhibitors show in vitro toxicity in ES cell lines as well as in vivo efficacy in ES xenografts as single agents. Expression of EWS/FLI1 or EWS/ERG oncogenic translocations sensitizes non-ES cells to ATR inhibitors. Our data shed light onto the sensitivity of ES to genotoxic agents, and identify ATR inhibitors as a potential therapy for Ewing Sarcomas. Impact Journals LLC 2016-08-26 /pmc/articles/PMC5312273/ /pubmed/27577084 http://dx.doi.org/10.18632/oncotarget.11643 Text en Copyright: © 2016 Nieto-Soler et al. http://creativecommons.org/licenses/by/2.5/ 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 Priority Research Paper
Nieto-Soler, Maria
Morgado-Palacin, Isabel
Lafarga, Vanesa
Lecona, Emilio
Murga, Matilde
Callen, Elsa
Azorin, Daniel
Alonso, Javier
Lopez, Andres J.
Nussenzweig, Andre
Fernandez-Capetillo, Oscar
Efficacy of ATR inhibitors as single agents in Ewing sarcoma
title Efficacy of ATR inhibitors as single agents in Ewing sarcoma
title_full Efficacy of ATR inhibitors as single agents in Ewing sarcoma
title_fullStr Efficacy of ATR inhibitors as single agents in Ewing sarcoma
title_full_unstemmed Efficacy of ATR inhibitors as single agents in Ewing sarcoma
title_short Efficacy of ATR inhibitors as single agents in Ewing sarcoma
title_sort efficacy of atr inhibitors as single agents in ewing sarcoma
topic Priority Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312273/
https://www.ncbi.nlm.nih.gov/pubmed/27577084
http://dx.doi.org/10.18632/oncotarget.11643
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