The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin
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José Luis Ordóñez1,4,*, Ana Teresa Amaral1,4,*, Angel M. Carcaboso2, David Herrero-Martín3, María del Carmen García-Macías4, Vicky Sevillano4, Diego Alonso4, Guillem Pascual-Pasto2, Laura San-Segundo4, Monica Vila-Ubach2, Telmo Rodrigues4, Susana Fraile4, Cristina Teodosio4, Agustín Mayo-Iscar5, Miguel Aracil6, Carlos María Galmarini6, Oscar M. Tirado3, Jaume Mora2 and Enrique de Álava1,4
1 Laboratory of Molecular Pathology, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Seville, Spain
2 Developmental Tumor Biology Laboratory, Preclinical Therapeutics and Drug Delivery Research Program, Hospital Sant Joan de Deu Barcelona, Spain
3 Sarcoma Research Group, Laboratori d’Oncología Molecular, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
4 Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer/Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Salamanca, Spain
5 Statistics and Operations Research Department, University of Valladolid, Spain
6 Cell Biology and Pharmacogenomics Department, Pharmamar, Madrid, Spain
* These authors have contributed equally to this work
José Luis Ordóñez García, email:
Enrique de Álava, email:
Keywords: Ewing sarcoma, PARP inhibitor, trabectedin, DNA damage, PDX models
Received: March 13, 2015 Accepted: May 13, 2015 Published: May 27, 2015
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.
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