Efficacy of ATR inhibitors as single agents in Ewing sarcoma
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Efficacy of ATR inhibitors as single agents in Ewing sarcoma. / Nieto-Soler, Maria; Morgado-Palacin, Isabel; Lafarga, Vanesa; Lecona, Emilio; Murga, Matilde; Callen, Elsa; Azorin, Daniel; Alonso, Javier; Lopez-Contreras, Andres J.; Nussenzweig, Andre; Fernandez-Capetillo, Oscar.
In: OncoTarget, Vol. 7, No. 37, 26.08.2016, p. 58759-58767.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Efficacy of ATR inhibitors as single agents in Ewing sarcoma
AU - Nieto-Soler, Maria
AU - Morgado-Palacin, Isabel
AU - Lafarga, Vanesa
AU - Lecona, Emilio
AU - Murga, Matilde
AU - Callen, Elsa
AU - Azorin, Daniel
AU - Alonso, Javier
AU - Lopez-Contreras, Andres J.
AU - Nussenzweig, Andre
AU - Fernandez-Capetillo, Oscar
PY - 2016/8/26
Y1 - 2016/8/26
N2 - 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.
AB - 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.
KW - ATR
KW - Ewing sarcoma
KW - replication stress
KW - DNA repair
KW - cancer
U2 - 10.18632/oncotarget.11643
DO - 10.18632/oncotarget.11643
M3 - Journal article
C2 - 27577084
VL - 7
SP - 58759
EP - 58767
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 37
ER -
ID: 169441305