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Inhibition of polo-like kinase 1 in glioblastoma multiforme induces mitotic catastrophe and enhances radiosensitisation

      Abstract

      Glioblastoma multiforme (GBM) is the most common primary brain tumour in the United States of America (USA) with a median survival of approximately 14 months. Low survival rates are attributable to the aggressiveness of GBM and a lack of understanding of the molecular mechanisms underlying GBM. The disruption of signalling pathways regulated either directly or indirectly by protein kinases is frequently observed in cancer cells and thus the development of inhibitors of specific kinases has become a major focus of drug discovery in oncology. To identify protein kinases required for the survival of GBM we performed a siRNA-based RNAi screen focused on the human kinome in GBM. Inhibition of the polo-like kinase 1 (PLK1) induced a reduction in the viability in two different GBM cell lines. To assess the potential of inhibiting PLK1 as a treatment strategy for GBM we examined the effects of a small molecule inhibitor of PLK1, GSK461364A, on the growth of GBM cells. PLK1 inhibition arrested cells in the mitotic phase of the cell cycle and induced cell kill by mitotic catastrophe. GBM engrafts treated with GSK461364A showed statistically significant inhibition of tumour growth. Further, exposure of different GBM cells to RNAi or GSK461364A prior to radiation resulted in an increase in their radiosensitivity with dose enhancement factor ranging from 1.40 to 1.53 with no effect on normal cells. As a measure of DNA double strand breaks, γH2AX levels were significantly higher in the combined modality as compared to the individual treatments. This study suggests that PLK1 is an important therapeutic target for GBM and can enhance radiosensitivity in GBM.

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      References

        • Preusser M.
        • de Ribaupierre S.
        • Wohrer A.
        • et al.
        Current concepts and management of glioblastoma.
        Ann Neurol. 2011; 70: 9-21
        • Stupp R.
        • Mason W.P.
        • van den Bent M.J.
        • et al.
        Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.
        N Engl J Med. 2005; 352: 987-996
        • Stupp R.
        • Hegi M.E.
        • Mason W.P.
        • et al.
        Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC–NCIC trial.
        Lancet Oncol. 2009; 10: 459-466
        • Futreal P.A.
        • Kasprzyk A.
        • Birney E.
        • Mullikin J.C.
        • Wooster R.
        • Stratton M.R.
        Cancer and genomics.
        Nature. 2001; 409: 850-852
        • Quant E.C.
        • Wen P.Y.
        Novel medical therapeutics in glioblastomas, including targeted molecular therapies, current and future clinical trials.
        Neuroimaging Clin N Am. 2010; 20: 425-448
        • Holand K.
        • Salm F.
        • Arcaro A.
        The phosphoinositide 3-kinase signaling pathway as a therapeutic target in grade IV brain tumors.
        Curr Cancer Drug Targets. 2011; 11: 894-918
        • MacKeigan J.P.
        • Murphy L.O.
        • Blenis J.
        Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance.
        Nat Cell Biol. 2005; 7: 591-600
        • Grueneberg D.A.
        • Li W.
        • Davies J.E.
        • et al.
        Kinase requirements in human cells: IV. Differential kinase requirements in cervical and renal human tumor cell lines.
        Proc Natl Acad Sci U S A. 2008; 105: 16490-16495
        • Manning B.D.
        Challenges and opportunities in defining the essential cancer kinome.
        Sci Signal. 2009; 2: pe15
        • Murrow L.M.
        • Garimella S.V.
        • Jones T.L.
        • Caplen N.J.
        • Lipkowitz S.
        Identification of WEE1 as a potential molecular target in cancer cells by RNAi screening of the human tyrosine kinome.
        Breast Cancer Res Treat. 2010; 122: 347-357
        • McCord A.M.
        • Jamal M.
        • Williams E.S.
        • Camphausen K.
        • Tofilon P.J.
        CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines.
        Clin Cancer Res. 2009; 15: 5145-5153
        • Buchanan I.M.
        • Scott T.
        • Tandle A.T.
        • et al.
        Radiosensitization of glioma cells by modulation of Met signalling with the hepatocyte growth factor neutralizing antibody, AMG102.
        J Cell Mol Med. 2011; 15: 1999-2006
        • Strebhardt K.
        Multifaceted polo-like kinases: drug targets and antitargets for cancer therapy.
        Nat Rev Drug Discov. 2010; 9: 643-660
        • Sigoillot F.D.
        • King R.W.
        Vigilance and validation: keys to success in RNAi screening.
        ACS Chem Biol. 2011; 6: 47-60
        • Sioud M.
        Promises and challenges in developing RNAi as a research tool and therapy.
        Methods Mol Biol. 2011; 703: 173-187
        • Martin S.E.
        • Wu Z.H.
        • Gehlhaus K.
        • et al.
        RNAi screening identifies TAK1 as a potential target for the enhanced efficacy of topoisomerase inhibitors.
        Curr Cancer Drug Targets. 2011; 11: 976-986
        • Bahassi el M.
        Polo-like kinases and DNA damage checkpoint: beyond the traditional mitotic functions.
        Exp Biol Med (Maywood). 2011; 236: 648-657
        • Degenhardt Y.
        • Lampkin T.
        Targeting Polo-like kinase in cancer therapy.
        Clin Cancer Res. 2010; 16: 384-389
        • Foong C.S.
        • Sandanaraj E.
        • Brooks H.B.
        • et al.
        Glioma-propagating cells as an in vitro screening platform: PLK1 as a case study.
        J Biomol Screen. 2012; 17: 1136-1150
        • Lee C.
        • Fotovati A.
        • Triscott J.
        • et al.
        Polo-like kinase 1 inhibition kills glioblastoma multiforme brain tumor cells in part through loss of SOX2 and delays tumor progression in mice.
        Stem Cells. 2012; 30: 1064-1075
        • Takai N.
        • Hamanaka R.
        • Yoshimatsu J.
        • Miyakawa I.
        Polo-like kinases (Plks) and cancer.
        Oncogene. 2005; 24: 287-291
        • Grinshtein N.
        • Datti A.
        • Fujitani M.
        • et al.
        Small molecule kinase inhibitor screen identifies polo-like kinase 1 as a target for neuroblastoma tumor-initiating cells.
        Cancer Res. 2011; 71: 1385-1395
        • Eckerdt F.
        • Yuan J.
        • Strebhardt K.
        Polo-like kinases and oncogenesis.
        Oncogene. 2005; 24: 267-276
        • Yamada S.
        • Ohira M.
        • Horie H.
        • et al.
        Expression profiling and differential screening between hepatoblastomas and the corresponding normal livers: identification of high expression of the PLK1 oncogene as a poor-prognostic indicator of hepatoblastomas.
        Oncogene. 2004; 23: 5901-5911
        • Steegmaier M.
        • Hoffmann M.
        • Baum A.
        • et al.
        BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo.
        Curr Biol. 2007; 17: 316-322
        • Ackermann S.
        • Goeser F.
        • Schulte J.H.
        • et al.
        Polo-like kinase 1 is a therapeutic target in high-risk neuroblastoma.
        Clin Cancer Res. 2011; 17: 731-741
        • Gerster K.
        • Shi W.
        • Ng B.
        • et al.
        Targeting polo-like kinase 1 enhances radiation efficacy for head-and-neck squamous cell carcinoma.
        Int J Radiat Oncol Biol Phys. 2010; 77: 253-260
        • Rodel F.
        • Keppner S.
        • Capalbo G.
        • et al.
        Polo-like kinase 1 as predictive marker and therapeutic target for radiotherapy in rectal cancer.
        Am J Pathol. 2010; 177: 918-929
        • Morales A.G.
        • Brassesco M.S.
        • Pezuk J.A.
        • et al.
        BI 2536-mediated PLK1 inhibition suppresses HOS and MG-63 osteosarcoma cell line growth and clonogenicity.
        Anticancer Drugs. 2011; 22: 995-1001
        • Qian Y.
        • Hua E.
        • Bisht K.
        • et al.
        Inhibition of Polo-like kinase 1 prevents the growth of metastatic breast cancer cells in the brain.
        Clin Exp Metastasis. 2011; 28: 899-908
        • Liu X.S.
        • Song B.
        • Elzey B.D.
        • et al.
        Polo-like kinase 1 facilitates loss of Pten tumor suppressor-induced prostate cancer formation.
        J Biol Chem. 2011; 286: 35795-35800
        • Ang C.
        • Guiot M.C.
        • Ramanakumar A.V.
        • Roberge D.
        • Kavan P.
        Clinical significance of molecular biomarkers in glioblastoma.
        Can J Neurol Sci. 2010; 37: 625-630
        • Koul D.
        PTEN signaling pathways in glioblastoma.
        Cancer Biol Ther. 2008; 7: 1321-1325
        • Lee J.J.
        • Kim B.C.
        • Park M.J.
        • et al.
        PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation.
        Cell Death Differ. 2011; 18: 666-677
        • Nappi T.C.
        • Salerno P.
        • Zitzelsberger H.
        • et al.
        Identification of Polo-like kinase 1 as a potential therapeutic target in anaplastic thyroid carcinoma.
        Cancer Res. 2009; 69: 1916-1923
        • Smits V.A.
        • Klompmaker R.
        • Arnaud L.
        • et al.
        Polo-like kinase-1 is a target of the DNA damage checkpoint.
        Nat Cell Biol. 2000; 2: 672-676
        • Olmos D.
        • Barker D.
        • Sharma R.
        • et al.
        Phase I study of GSK461364, a specific and competitive Polo-like kinase 1 inhibitor, in patients with advanced solid malignancies.
        Clin Cancer Res. 2011; 17: 3420-3430