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

Nan Li, Dustin J. Maly, Yvan H. Chanthery, Daniel W. Sirkis, Jean L. Nakamura, Mitchel S. Berger, C. David James, Kevan M. Shokat, William A. Weiss, Anders I. Persson*

*Corresponding author for this work

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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 pro fi les 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 ef fi cacy of radiotherapy by targeting radioresistant TPCs in human GBMs.

Original languageEnglish (US)
Pages (from-to)419-428
Number of pages10
JournalMolecular cancer therapeutics
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Li, N., Maly, D. J., Chanthery, Y. H., Sirkis, D. W., Nakamura, J. L., Berger, M. S., James, C. D., Shokat, K. M., Weiss, W. A., & Persson, A. I. (2015). Radiotherapy followed by aurora kinase inhibition targets tumor-propagating cells in human glioblastoma. Molecular cancer therapeutics, 14(2), 419-428. https://doi.org/10.1158/1535-7163.MCT-14-0526