期刊
ONCOTARGET
卷 7, 期 37, 页码 58759-58767出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.11643
关键词
ATR; Ewing sarcoma; replication stress; DNA repair; cancer
资金
- Fundacion Botin
- Banco Santander through its Santander Universities Global Division
- MINECO [SAF2014-57791-REDC, SAF2014-59498-R]
- Fundacio La Marato de TV3
- Howard Hughes Medical Institute
- European Research Council [ERC-617840]
- Intramural Research Program of the NIH
- National Cancer Institute
- Center for Cancer Research
- Ellison Medical Foundation Senior Scholar in Aging
- Alex Lemonade Stand Foundation Award
- Asociacion Pablo Ugarte
- ASION-La Hucha de Tomas
- Fundacion La Sonrisa de Alex
- Instituto de Salud Carlos III [PI12/00816]
- Instituto de Salud Carlos III (Spanish Cancer Network RTICC) [RD12/0036/0027]
- Danish National Research Foundation [DNRF115]
- Danish Council for Independent Research (Sapere Aude, DFF-Starting Grant)
- Danish Cancer Society [KBVU-2014]
- The Danish Cancer Society [R90-A6031] Funding Source: researchfish
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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