Radiotherapy followed by aurora kinase inhibition targets tumor-propagating cells in human glioblastoma

Mol Cancer Ther. 2015 Feb;14(2):419-28. doi: 10.1158/1535-7163.MCT-14-0526. Epub 2014 Dec 18.


Glioblastoma (GBM) is the most common malignant primary brain tumor. Radiotherapy fails to eliminate subpopulations of stem-like tumor-propagating cells (TPC), 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 nonselective 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 before radiation. Our results indicate that AURK inhibition, subsequent to radiation, may enhance the efficacy of radiotherapy by targeting radioresistant TPCs in human GBMs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Aurora Kinases / antagonists & inhibitors*
  • Aurora Kinases / metabolism
  • Biomarkers, Tumor / metabolism
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / pathology
  • Brain Neoplasms / radiotherapy*
  • Cell Cycle Checkpoints / drug effects
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • Glioblastoma / drug therapy*
  • Glioblastoma / pathology
  • Glioblastoma / radiotherapy*
  • Histones / metabolism
  • Humans
  • Membrane Glycoproteins / metabolism
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology*
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Radiation Tolerance / drug effects
  • Xenograft Model Antitumor Assays


  • Biomarkers, Tumor
  • Histones
  • Membrane Glycoproteins
  • PDPN protein, human
  • Protein Kinase Inhibitors
  • Aurora Kinases