Cargando…
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...
Autores principales: | , , , , , , , , , , |
---|---|
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 |
_version_ | 1782508173029015552 |
---|---|
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. |
format | Online Article Text |
id | pubmed-5312273 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT nietosolermaria efficacyofatrinhibitorsassingleagentsinewingsarcoma AT morgadopalacinisabel efficacyofatrinhibitorsassingleagentsinewingsarcoma AT lafargavanesa efficacyofatrinhibitorsassingleagentsinewingsarcoma AT leconaemilio efficacyofatrinhibitorsassingleagentsinewingsarcoma AT murgamatilde efficacyofatrinhibitorsassingleagentsinewingsarcoma AT callenelsa efficacyofatrinhibitorsassingleagentsinewingsarcoma AT azorindaniel efficacyofatrinhibitorsassingleagentsinewingsarcoma AT alonsojavier efficacyofatrinhibitorsassingleagentsinewingsarcoma AT lopezandresj efficacyofatrinhibitorsassingleagentsinewingsarcoma AT nussenzweigandre efficacyofatrinhibitorsassingleagentsinewingsarcoma AT fernandezcapetillooscar efficacyofatrinhibitorsassingleagentsinewingsarcoma |