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oai:repisalud.isciii.es:20.500.12105/96152025-06-17T10:22:10Zcom_20.500.12105_2173com_20.500.12105_2051com_20.500.12105_2052col_20.500.12105_19597col_20.500.12105_19616

00925njm 22002777a 4500 dc Nieto-Soler, Maria author Morgado-Palacin, Isabel author Lafarga, Vanesa author Lecona, Emilio author Murga, Matilde author Callen, Elsa author Azorin, Daniel author Alonso, Javier author Lopez-Contreras, Andres J author Nussenzweig, Andre author Fernandez-Capetillo, Oscar author 2016-09-13 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. Oncotarget. 2016 Sep 13;7(37):58759-58767. 10.18632/oncotarget.11643 1949-2553 1949-2553 Oncotarget 27577084 http://hdl.handle.net/20.500.12105/9615 ATR DNA repair Ewing sarcoma Cancer Replication stress Efficacy of ATR inhibitors as single agents in Ewing sarcoma