Abstract
Despite the availability of hundreds of drugs, there is little data on the efficacy of these agents in the extremely heterogeneous populations of tumor cells observed in glioblastoma. In this study, a high-throughput compound-screening (HTS) assay was used to identify drug sensitivities in a panel of 15 glioblastoma stem cell (GSC) lines, which are representative of the classic cancer genome atlas (TCGA) molecular subtypes, to 21 compounds in Published Protein Kinase Inhibitor Set (PKSI, GSK). This HTS screen identified sensitivity of GSCs to inhibitors of polo like kinase-1 (PLK-1), a key regulator of mitosis. Given that PLK-1 is often overexpressed in a broad spectrum of cancers, and with highest expression levels being correlated with poor prognosis in several cancer types, we further verified the HTS result with the second-generation PLK1 inhibitor volasertib as a single agent or in combination with ionizing radiation. Efficacy of volasertib was analyzed by Cell-Titer Glo 5 days after treatment. Molecular and cellular changes were approached by immunoblotting and flow cytometry. In vitro studies showed that volasertib inhibited cell viability with an IC50 ranging from 8.2nM to 4.36 µM. Volasertib induced G2/M arrest accompanied by high levels of PLK-1, Aurora B and phospho-histone 3 and prominent cleaved poly ADP ribose polymerase (PARP) in a dose- and time-dependent manner. Colony formation assay demonstrated that volasertib plus ionizing radiation had synergistic effects on colony formation inhibition, suggesting that GSCs arrested in M phase by volasertib are more sensitive to ironizing radiation. Intracranial xenograft models showed that the combination of volasertib (10mg/Kg) and 10Gy radiation significantly inhibited GSC tumor growth and prolonged median survival when compared with radiation alone. Taken together, our results reinforce the potential therapeutic efficacy of volasertib in combination with radiation therapy for the treatment of glioblastoma.
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