Oncotarget

Priority Research Papers:

Efficacy of ATR inhibitors as single agents in Ewing sarcoma

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

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Oncotarget. 2016; 7:58759-58767. https://doi.org/10.18632/oncotarget.11643

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Abstract

Maria Nieto-Soler1,*, Isabel Morgado-Palacin1,*, Vanesa Lafarga1,*, Emilio Lecona1, Matilde Murga1, Elsa Callen2, Daniel Azorin3, Javier Alonso4, Andres J. Lopez-Contreras5, Andre Nussenzweig2 and Oscar Fernandez-Capetillo1,6

1 Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

2 Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, Maryland, USA

3 Department of Pathology, Hospital Universitario Niño Jesus, Madrid, Spain

4 Pediatric Solid Tumor Laboratory, Institute of Rare Disease Research, ISCIII, Madrid, Spain

5 Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Denmark

6 Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden

* These authors have equally contributed to this work

Correspondence to:

Oscar Fernandez-Capetillo, email:

Keywords: ATR, Ewing sarcoma, replication stress, DNA repair, cancer

Received: July 20, 2016 Accepted: August 21, 2016 Published: August 26, 2016

Abstract

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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