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dc.contributor.authorZahonero, Cristina 
dc.contributor.authorAguilera, Pilar
dc.contributor.authorRamírez-Castillejo, Carmen
dc.contributor.authorPajares, Marta
dc.contributor.authorBolos, Victoria 
dc.contributor.authorCantero, Diana
dc.contributor.authorPerez-Nuñez, Angel
dc.contributor.authorHernández-Laín, Aurelio
dc.contributor.authorSepúlveda, Juan Manuel
dc.contributor.authorSanchez-Gomez, Pilar
dc.identifier.citationMol Cancer Ther . 2015 Jul;14(7):1548-58es_ES
dc.description.abstractGlioblastomas (GBM) are devastating tumors in which there has been little clinical improvement in the last decades. New molecularly directed therapies are under development. EGFR is one of the most promising targets, as this receptor is mutated and/or overexpressed in nearly half of the GBMs. However, the results obtained with first-generation tyrosine-kinase inhibitors have been disappointing with no clear predictive markers of tumor response. Here, we have tested the antitumoral efficacy of a second-generation inhibitor, dacomitinib (PF299804, Pfizer), that binds in an irreversible way to the receptor. Our results confirm that dacomitinib has an effect on cell viability, self-renewal, and proliferation in EGFR-amplified ± EGFRvIII GBM cells. Moreover, systemic administration of dacomitinib strongly impaired the in vivo tumor growth rate of these EGFR-amplified cell lines, with a decrease in the expression of stem cell-related markers. However, continuous administration of the compound was required to maintain the antitumor effect. The data presented here confirm that dacomitinib clearly affects receptor signaling in vivo and that its strong antitumoral effect is independent of the presence of mutant receptor isoforms although it could be affected by the PTEN status (as it is less effective in a PTEN-deleted GBM line). Dacomitinib is being tested in second line for EGFR-amplified GBMs. We hope that our results could help to select retrospectively molecular determinants of this response and to implement future trials with dacomitinib (alone or in combination with other inhibitors) in newly diagnosed GBMs.es_ES
dc.description.sponsorshipThis work was supported by grants from the Fundación Mutua-madrileña (FMM2011/89) to J.M. Sepúlveda and from Ministerio de Economía y Competitividad, Fondo de Investigación Sanitaria (FIS): PI12/00775 to P. Sánchez-Gómez and PI13/01258 to A. Hernández-Laín, and from Ministerio de Economía y Competitividad, Red Temática de Investigación Cooperativa en Cancer (RTICC) (RD12/0036/0027) to J.M. Sepúlveda, P. Sánchez-Gómez, A. Pérez-Núñez and A. Hernández-Laín.es_ES
dc.publisherAmerican Association for Cancer Researches_ES
dc.subject.meshXenograft Model Antitumor Assays es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshBlotting, Westernes_ES
dc.subject.meshCell Survival es_ES
dc.subject.meshDose-Response Relationship, Druges_ES
dc.subject.meshDrug Screening Assays, Antitumores_ES
dc.subject.meshErbB Receptors es_ES
dc.subject.meshGene Amplification es_ES
dc.subject.meshGlioblastoma es_ES
dc.subject.meshHumans es_ES
dc.subject.meshMice, Nude es_ES
dc.subject.meshPhosphorylation es_ES
dc.subject.meshQuinazolinones es_ES
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction es_ES
dc.subject.meshSignal Transduction es_ES
dc.subject.meshSurvival Analysis es_ES
dc.subject.meshTime Factors es_ES
dc.subject.meshTumor Burden es_ES
dc.subject.meshTumor Cells, Culturedes_ES
dc.titlePreclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma.es_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.contributor.funderFundación Mutua-madrileñaes_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderFondo de Investigaciones Sanitariases_ES
dc.contributor.funderRed Temática de Investigación Cooperativa en Cáncer (España)es_ES
dc.identifier.journalMolecular cancer therapeuticses_ES
dc.repisalud.centroISCIII::Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC)es_ES

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Atribución-NoComercial-CompartirIgual 4.0 Internacional
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