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Title: The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin
Authors: Ordóñez, José Luis
Amaral, Ana Teresa
Carcaboso, Ángel M.
Herrero Martín, David
García Macías, María del Carmen
Alonso, Diego
Pascual Pastor, Guillem
San Segundo, Laura
Vila Ubach, Mónica
Rodrigues, Telmo
Fraile, Susana
Teodosio, Cristina
Mayo Iscar, Agustín
Aracil, Miguel
Galmarini, Carlos María
Tirado, Oscar M.
Mora, Jaume
Álava, Enrique de
Issue Date: 2015
Publisher: Impact Journals
Description: Producción Científica
Citation: Oncotarget, 2015, 6 (22), p. 18875-90
Abstract: Recent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing EWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents. Trabectedin is an antitumoral agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage. Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh disrupts the DDR machinery. Thus, given the impact and apparent specificity of both agents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity in ES, we decided to explore the activity of combining PARPinh and Trabectedin in in vitro and in vivo experiments. The combination of Olaparib and Trabectedin was found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, and the accumulation of G2/M. The drug combination also enhanced γH2AX intranuclear accumulation as a result of DNA damage induction, DNA fragmentation and global DDR deregulation, while EWSR1-FLI1 target expression remained unaffected. The effect of the drug combination was corroborated in a mouse xenograft model of ES and, more importantly, in two ES patient-derived xenograft (PDX) models in which the tumors showed complete regression. In conclusion, the combination of the two agents leads to a biologically significant deregulation of the DDR machinery that elicits relevant antitumor activity in preclinical models and might represent a promising therapeutic tool that should be further explored for translation to the clinical setting.
Keywords: Sarcoma
ISSN: 1949-2553
Peer Review: SI
DOI: 10.18632/oncotarget.4303
Sponsor: Ministerio de Economía y Competitividad (PI081828)
Ministerio de Economía y Competitividad (RD06/0020/0059 )
Ministerio de Economía y Competitividad (RD12/0036/0017)
Ministerio de Economía y Competitividad (PT13/0010/0056)
Publisher Version:
Language: eng
Rights: info:eu-repo/semantics/openAccess
Appears in Collections:DEP24 - Artículos de revista

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