title: Radiotherapy followed by aurora kinase inhibition targets tumor-propagating cells in human glioblastoma.
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 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.
authors.affiliation: Department of Neurology, University of California, San Francisco, California. Department of Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, California. Sandler Neurosciences Center, University of California, San Francisco, California.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Chemistry, University of Washington, Seattle, Washington.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Maly
authors.affiliation: Department of Neurology, University of California, San Francisco, California. Department of Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, California. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Yvan H
authors.initials: YH
authors.lastname: Chanthery
authors.affiliation: Department of Neurology, University of California, San Francisco, California. Department of Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, California. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Sirkis
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California. Department of Radiation Oncology, University of California, San Francisco, California.
authors.forename: Jean L
authors.initials: JL
authors.lastname: Nakamura
authors.affiliation: Department of Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, California. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.affiliation: Department of Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, California. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.affiliation: Chemistry and Chemical Biology Graduate Program, Howard Hughes Medical Institute, University of California, San Francisco, California.
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.affiliation: Department of Neurology, University of California, San Francisco, California. Department of Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, California. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.affiliation: Department of Neurology, University of California, San Francisco, California. Department of Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, California. Sandler Neurosciences Center, University of California, San Francisco, California. Anders.Persson@ucsf.edu.
authors.forename: Anders I
authors.initials: AI
authors.lastname: Persson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064127:Aurora Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011836:Radiation Tolerance / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000098853:Podoplanin
chemical_list: D064127:Aurora Kinases; D014408:Biomarkers, Tumor; D006657:Histones; D008562:Membrane Glycoproteins; D047428:Protein Kinase Inhibitors; C117468:PDPN protein, human; D000098853:Podoplanin