Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/9615
Efficacy of ATR inhibitors as single agents in Ewing sarcoma
Nieto-Soler, Maria | Morgado-Palacin, Isabel | Lafarga, Vanesa CNIO | Lecona, Emilio | Murga, Matilde CNIO | Callen, Elsa | Azorin, Daniel | Alonso, Javier ISCIII | Lopez-Contreras, Andres J | Nussenzweig, Andre | Fernandez-Capetillo, Oscar CNIO
Oncotarget. 2016 Sep 13;7(37):58759-58767.
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.
Animals | Antineoplastic Agents | Apoptosis | Ataxia Telangiectasia Mutated Proteins | Bone Neoplasms | Cell Line, Tumor | DNA Damage | Gene Expression Regulation, Neoplastic | Humans | Male | Mice | Mice, SCID | RNA, Small Interfering | RNA-Binding Protein EWS | Sarcoma, Ewing
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