title: Efficacy of ATR inhibitors as single agents in Ewing sarcoma.
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.
authors: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Maria
authors: M
authors: Nieto-Soler
authors: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Isabel
authors: I
authors: Morgado-Palacin
authors: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Vanesa
authors: V
authors: Lafarga
authors: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Emilio
authors: E
authors: Lecona
authors: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Matilde
authors: M
authors: Murga
authors: Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, Maryland, USA.
authors: Elsa
authors: E
authors: Callen
authors: Department of Pathology, Hospital Universitario Niño Jesus, Madrid, Spain.
authors: Daniel
authors: D
authors: Azorin
authors: Pediatric Solid Tumor Laboratory, Institute of Rare Disease Research, ISCIII, Madrid, Spain.
authors: Javier
authors: J
authors: Alonso
authors: Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Denmark.
authors: Andres J
authors: AJ
authors: Lopez-Contreras
authors: Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, Maryland, USA.
authors: Andre
authors: A
authors: Nussenzweig
authors: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.|Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors: Oscar
authors: O
authors: Fernandez-Capetillo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D034741:RNA, Small Interfering / Q000235:genetics; D034802:RNA-Binding Protein EWS / Q000235:genetics; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D034802:RNA-Binding Protein EWS; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATR; DNA repair; Ewing sarcoma; cancer; replication stress