RT info:eu-repo/semantics/article
T1 The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin
A1 Ordóñez García, José Luis
A1 Amaral, Ana Teresa
A1 Montero Carcaboso, Ángel
A1 Herrero Martín, David
A1 García Macías, María del Carmen
A1 Alonso López, Diego
A1 Pascual Pastor, Guillem
A1 San Segundo, Laura
A1 Vila Ubach, Mónica
A1 Rodrigues, Telmo
A1 Fraile, Susana
A1 Teodosio, Cristina
A1 Mayo Iscar, Agustín
A1 Aracil, Miguel
A1 Galmarini, Carlos María
A1 Martínez Tirado, Oscar
A1 Mora Graupera, Jaume
A1 Álava, Enrique de
K1 Sarcoma
AB Recent preclinical evidence has suggested that Ewing Sarcoma (ES) bearingEWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) incombination with DNA damage repair (DDR) agents. Trabectedin is an antitumoralagent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage.Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinhdisrupts the DDR machinery. Thus, given the impact and apparent specificity of bothagents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity inES, we decided to explore the activity of combining PARPinh and Trabectedin in invitro and in vivo experiments. The combination of Olaparib and Trabectedin wasfound to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, andthe accumulation of G2/M. The drug combination also enhanced γH2AX intranuclearaccumulation as a result of DNA damage induction, DNA fragmentation and global DDRderegulation, while EWSR1-FLI1 target expression remained unaffected. The effect ofthe drug combination was corroborated in a mouse xenograft model of ES and, moreimportantly, in two ES patient-derived xenograft (PDX) models in which the tumorsshowed complete regression. In conclusion, the combination of the two agents leadsto a biologically significant deregulation of the DDR machinery that elicits relevantantitumor activity in preclinical models and might represent a promising therapeutictool that should be further explored for translation to the clinical setting.
PB Impact Journals
SN 1949-2553
YR 2015
FD 2015
LK http://uvadoc.uva.es/handle/10324/21677
UL http://uvadoc.uva.es/handle/10324/21677
LA eng
NO Oncotarget, 2015, 6 (22), p. 18875-90
NO Producción Científica
DS UVaDOC
RD 14-oct-2024