In vivo evidences for the therapeutic effectiveness of Dacomitinib in glioblastoma

Cristina Zahonero1, Pilar Aguilera1; Carmen Ramírez-Castillejo1,2, Diana Cantero3; Angel Pérez3, Aurelio Hernández-Laín3, M. Victoria Bolós4, Pilar Sánchez-Gómez1, Juan M. Sepúlveda3

1.Neuro-oncology Unit, Instituto de Salud Carlos III-UFIEC, Madrid, Spain

2.Biochemistry Department. Universidad Politécnica de Madrid, Madrid, Spain

3.Multidisciplinar Neurooncolgy Unit, Hospital Universitario 12 de Octubre, Madrid, Spain

4.fizer Oncoloy, Madrid, Spain

Glioblastomas (GBMs) are devastating tumors in which there has been little clinical improvement in the last decades. Our results confirm that dacomitinib has an effect on cell viability, self-renewal and proliferation in EGFR amplified +/-EGFRvIII GBM cells. 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. Dacomitinib reduced the cellularity, and the number of mitotic cells per field in the flank tumors, whereas the number of Caspase 3 positive cells per field was increased. However, continuous administration of the compound was required to maintain the antitumor effect. The data presented here confirms 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). Moreover, Intracranial GBM growth was also impaired by systemic Dacomitinib treatment. The tumor burden was confirmed by vimentin staining of tumors formed and contrast-enhanced MRI images. Animal survival evaluated by Kaplan-Meier survival curve demonstrated that EGFR inhibition prolonged the survival of the GBM-bearing animals. Subsequent analysis of the tumor tissue confirmed that there was a significant reduction of proliferation and a clear induction of apoptosis in dacomitinib-treated animals. Moreover, we confirmed the results obtained in the flank as we observed a strong downregulation of the phosphorylation of EGFR and its downstream target. 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.​