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Efficacy of ATR inhibitors as single agents in Ewing sarcoma

Publikation: Bidrag til tidsskriftTidsskriftartikel

Dokumenter

Maria Nieto-Soler, Isabel Morgado-Palacin, Vanesa Lafarga, Emilio Lecona, Matilde Murga, Elsa Callen, Daniel Azorin, Javier Alonso, Andres J. Lopez-Contreras, Andre Nussenzweig, Oscar Fernandez-Capetillo

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.
OriginalsprogEngelsk
TidsskriftOncoTarget
Vol/bind7
Tidsskriftsnummer37
Sider (fra-til)58759-58767
ISSN1949-2553
DOI
StatusUdgivet - 26 aug. 2016

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