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Preclinical test of dacomitinib, an irreversible EGFR inhibitor, confirms its effectiveness for glioblastoma.

Cristina Zahonero1, Pilar Aguilera1, Carmen Ramírez-Castillejo1, Diana Cantero2, Angel Pérez2, Aurelio Hernández-Laín2, M. Victoria Bolós3, P. Sánchez-Gómez1, Juan M. Sepúlveda2

1 Neuro-oncologyUnit, Instituto de Salud Carlos III-UFIEC, Madrid, Spain
2 Unidad Multidisciplinar de Neurooncología, Hospital Universitario 12 de Octubre, Madrid, Spain
3PfizerOncoloy, Madrid. Spain

Glioblastoma (GBM) is the most common and aggressive tumor that affects the Central Nervous System. Since nearly 50% of primary GBMs are characterized by the presence of mutations and/or the overexpression of epidermal growth factor receptor (EGFR), its inhibition is one of the most attractive therapeutic strategies. However, first-generation EGFR inhibitors have produced poor results with brain tumors in clinical trials. For this reason, new second-generation tyrosine-kinase inhibitors have been designed. Here, we have tested a new molecule, dacomitinib (PF-00299804, Pfizer), that binds irreversibly to EGFR. Indeed, it has been proved to be active in erlotinib (Roche) and gefitinib (AstraZeneca)-resistant nonclinical models of advanced lung tumors. Our group has proved that dacomitinib decreases cell viability, self-renewal and proliferation of primary GBM cell lines with EGFR amplification. Here we show that systemic administration of dacomitinib reduces tumor volume and increases survival in in vivo models. The effect is evident in EGFR-amplified models, regardless of the presence of EGFR mutations, but it is less efficient in the absence of PTEN function. Interestingly, tumors that respond to dacomitinib show a decrease in stem-cell markers. However, terminal differentiation does not seem to occur after EGFR inhibition. In agreement with this, we show that a continuous administration of this compound is needed in order to maintain the antitumor effect. Simultaneously to our pre-clinical research, a phase II clinical assay with dacomitinib has been performed in recurrent GBM patients with EGFR amplification and/or in the presence of the truncated isoform EGFR-vIII (EudraCT: 2011-004671-37; GEINO-11). We hope that our results could help to retrospectively analyze the results of this clinical assay and, more importantly, to determine the predictive markers for future clinical trials with dacomitinib.

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