Radiotherapy followed by aurora kinase inhibition target tumor-propagating cells in human glioblastoma
Menée in vitro et à l'aide d'une xénogreffe de glioblastome humain sur un modèle murin, cette étude identifie des inhibiteurs de kinase Aurora et évalue leur efficacité pour supprimer la radiorésistance des cellules souches tumorales
Glioblastoma (GBM) is the most common malignant primary brain tumor. Radiotherapy fails to eliminate subpopulations of stem-like tumor-propagating cells (TPCs), resulting in tumor regrowth. To identify kinases that promote TPC self-renewal rather than increasing proliferation in human GBM cultures, we screened a library of 54 non-selective tool compounds and determined their kinase inhibitor profiles in vitro. Most compounds inhibited aurora kinase (AURK) activity and blocked TPC self-renewal, while inducing GBM cell polynucleation and apoptosis. To prevent regrowth by TPCs, we used a priming dose of radiation followed by incubation with the pan-AURK inhibitor VX680 to block self-renewal and induce apoptosis in GBM cultures. In mice xenografted with human GBM cells, radiotherapy followed by VX680 treatment resulted in reduced tumor growth and increased survival relative to either monotherapy alone or VX680 treatment prior to radiation. Our results indicate that AURK inhibition, subsequent to radiation, may enhance the efficacy of radiotherapy by targeting radioresistant TPCs in human GBMs.
http://mct.aacrjournals.org/content/early/2014/12/18/1535-7163.MCT-14-0526.abstract