The unexpected role of Aurora A kinase in glioblastoma recurrences

[en] The main obstacle for the cure of glioblastoma (GBM) is systematic tumor recurrence after treatment. More than 90 % of GBM tumors are indeed recurrent within 5 years after diagnosis and treatment. We urgently need new therapies to specifically address these deadly relapses. A major advance in the understanding of GBM recurrence is the identification of GBMInitiating Cells (GIC), characterized by their abilities for self-renewal, multilineage differentiation, and proliferation. It appears that these features of GIC could be modulated by the mitotic kinase Aurora A (AurA). Indeed, besides its role in mitosis, AurA has recently been identified to regulate alternative functions like cell polarity, asymmetric cell division, and epithelial to mesenchymal transition. All these properties may help explain GBM therapeutic resistance and recurrence. In this review, we make the hypothesis that AurA could significantly contribute to GBM recurrences and we focus on the possible roles of AurA in GIC.

Research Center/Unit :

Giga-Neurosciences - ULiège

Disciplines :

Oncology

Author, co-author :

Willems, Estelle ; Université de Liège - ULiège > Doct. sc. bioméd. & pharma. (paysage)

LOMBARD, Arnaud ; Centre Hospitalier Universitaire de Liège - CHU > Service de neurochirurgie

Dedobbeleer, Matthias ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biochimie et physiologie générales, et biochimie humaine

Goffart, Nicolas

ROGISTER, Bernard ; Centre Hospitalier Universitaire de Liège - CHU > Service de neurologie

Language :

English

Title :

The unexpected role of Aurora A kinase in glioblastoma recurrences

Publication date :

2017

Journal title :

Targeted Oncology

ISSN :

1776-2596

eISSN :

1776-260X

Publisher :

Springer, Germany

Volume :

Pages :

11-18

Peer reviewed :

Peer Reviewed verified by ORBi

Name of the research project :

Implication of AurA kinase in GBM cells chemotaxis in response to the production of CXCL12 in the subventricular zones

Funders :

F.R.S.-FNRS - Fonds de la Recherche Scientifique
Fonds Léon Fredericq

Available on ORBi :

since 07 July 2018

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Bibliography

Ostrom QT, Gittleman H, Liao P, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neurol Oncol. 2014;16:iv1–63. doi:10.1093/neuonc/nou223.
Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131:1–18. doi:10.1007/s00401-016-1545-1.
Cuddapah VA, Robel S, Watkins S, Sontheimer H. A neurocentric perspective on glioma invasion. Nat Rev Neurosci. 2014;15:455–65. doi:10.1038/nrn3765.
Fine H, Dear K, Loeffler J, et al. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer. 1993;71:2585–97.
Hegi ME, Diserens A-C, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997–1003. doi:10.1056/NEJMoa043331.
Stupp R, Hegi ME, Mason WP, 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;10:459–66. doi:10.1016/S1470-2045(09)70025-7.
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96. doi:10.1056/NEJMoa043330.
Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63:5821–8. doi:10.1038/nature03128.
Lathia J, Mack S, Mulkearns-Hubert E, et al. Cancer stem cells in glioblastoma. Genes Dev. 2015;29:1203–17. doi:10.1101/gad.261982.115.tumors.
Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64:7011–21. doi:10.1158/0008-5472.CAN-04-1364.
Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature. 2004;432:396–401. doi:10.1038/nature03128.
Zhou Z, Ping Y, Yu S, et al. A novel approach to the identification and enrichment of cancer stem cells from a cultured human glioma cell line. Cancer Lett. 2015;281:92–9. doi:10.1016/j.canlet.2009.02.033.
Chaichana K, Zamora-Berridi G, Camara-Quintana J, Quiñones-Hinojosa A. Neurosphere assays: growth factors and hormone differences in tumor and nontumor studies. Stem Cells. 2006;24:2851–7. doi:10.1634/stemcells.2006-0399.
Piccirillo SGM, Combi R, Cajola L, et al. Distinct pools of cancer stem-like cells coexist within human glioblastomas and display different tumorigenicity and independent genomic evolution. Oncogene. 2009;28:1807–11. doi:10.1038/onc.2009.27.
Goffart N, Dedobbeleer M, Rogister B. Glioblastoma stem cells: new insights in therapeutic strategies. Future Neurol. 2014;9:1–15. doi:10.2217/fnl.14.56.
U.S. National Institutes of Health. ClinicalTrials.gov Homepage. http://www.clinicaltrials.gov (2013). Accessed 6 July 2016.
Takebe N, Miele L, Harris PJ, et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol. 2015;12:445–64. doi:10.1038/nrclinonc.2015.61.
Takezaki T, Hide T, Takanaga H, et al. Essential role of the Hedgehog signaling pathway in human glioma-initiating cells. Cancer Sci. 2011;102:1306–12. doi:10.1111/j.1349-7006.2011.01943.x.
Frei K, Gramatzki D, Tritschler I, Schroeder JJ, et al. Transforming growth factor-β pathway activity in glioblastoma. Oncotarget. 2015;6:5963–77. doi:10.18632/oncotarget.3467.
Ikushima H, Todo T, Ino Y, et al. Autocrine TGF-b signaling maintains tumorigenicity of glioma-initiating cells through sry-related HMG-Box factors. Cell Stem Cell. 2016;5:504–14. doi:10.1016/j.stem.2009.08.018.
Kim Y, Kim KH, Lee H, et al. Wnt activation is implicated in glioblastoma radioresistance. Lab Investig. 2012;92:466–73. doi:10.1158/1538-7445.AM2012-3458.
González-Gómez P, Anselmo NP, Mira H. BMPs as therapeutic targets and biomarkers in astrocytic glioma. Biomed Res Int. 2014;2014:549742. doi:10.1155/2014/549742.
Piccirillo SGM, Reynolds BA, Zanetti N, et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature. 2006;444:761–5. doi:10.1038/nature05349.
Liu G, Yuan X, Zeng Z, et al. Analysis of gene expression and chemoresistance of CD133(+)cancer stem cells in glioblastoma. Mol Cancer. 2006;5:67. doi:10.1186/1476-4598-5-67.
Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756–60. doi:10.1038/nature05236.
Venere M, Hamerlik P, Wu Q, et al. Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells. Cell Death Differ. 2014;21:258–69. doi:10.1038/cdd.2013.136.
Barone A, Sengupta R, Warrington NM, et al. Combined VEGF and CXCR4 antagonism targets the GBM stem cell population and synergistically improves survival in an intracranial mouse model of glioblastoma. Oncotarget. 2014;5:9811–22. doi:10.18632/oncotarget.2443.
Lim DA, Cha S, Mayo MC, et al. Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype. Neurol Oncol. 2007;9:424–9. doi:10.1215/15228517-2007-023.
Goffart N, Kroonen J, Di Valentin E, et al. Adult mouse subventricular zones stimulate glioblastoma stem cells specific invasion through CXCL12/CXCR4 signaling. Neurol Oncol. 2014;17:81–94. doi:10.1093/neuonc/nou144.
Ehtesham M, Winston JA, Kabos P, Thompson RC. CXCR4 expression mediates glioma cell invasiveness. Oncogene. 2006;25:2801–6. doi:10.1038/sj.onc.1209302.
Do Carmo A, Patricio I, Cruz MT, et al. CXCL12/CXCR4 promotes motility and proliferation of glioma cells. Cancer Biol Ther. 2010;9:9–10. doi:10.5214/ans.0972-7531.1017207.
De Almeida Sassi F, Lunardi Brunetto A, Schwartsmann G, Roesler RAAL. Glioma revisited: from neurogenesis and cancer stem cells to the epigenetic regulation of the niche. J Oncol. 2012;537861:1–18. doi:10.1155/2012/537861.
Adeberg S, König L, Bostel T, et al. Glioblastoma recurrence patterns after radiation therapy with regard to the subventricular zone. Int J Radiat Oncol Biol Phys. 2016;90:886–93. doi:10.1016/j.ijrobp.2014.07.027.
Jafri NF, Clarke JL, Weinberg V, et al. Relationship of glioblastoma multiforme to the subventricular zone is associated with survival. Neurol Oncol. 2013;15:91–6. doi:10.1093/neuonc/nos268.
Heddleston JM, Li Z, Hjelmeland AB, Rich JN. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle. 2009;8:3274–84. doi:10.1016/j.surg.2006.10.010.
Chen J, Li Y, Yu T-S, McKay RM, Burns DK, Kernie M, et al. A restricted cell population propagates glioblastoma growth following chemotherapy. Nature. 2012;488:522–6. doi:10.1038/nature11287.
Gómez-López S, Lerner RG, Petritsch C. Asymmetric cell division of stem and progenitor cells during homeostasis and cancer. Cell Mol Life Sci. 2014;71:575–97. doi:10.1007/s00018-013-1386-1.
Compton DA. Mechanism of aneuploidy. Curr Opin Cell Biol. 2011;23:109–13. doi:10.1016/j.ceb.2010.08.007.
Hochegger H, Hégarat N, Pereira-Leal JB. Aurora at the pole and equator: overlapping functions of Aurora kinases in the mitotic spindle. Open Biol. 2013;3:120185. doi:10.1098/rsob.120185.
Nikonova AS, Astsaturov I, Serebriiskii IG, et al. Aurora A kinase (AURKA) in normal and pathological cell division. Cell Mol Life Sci. 2013;70:661–87. doi:10.1007/s00018-012-1073-7.
Sakakura C, Hagiwara A, Yasuoka R, et al. Tumour-amplified kinase BTAK is amplified and overexpressed in gastric cancers with possible involvement in aneuploid formation. Br J Cancer. 2001;84:824–31. doi:10.1054/bjoc.2000.1684.
Vader G, Lens SMA. The Aurora kinase family in cell division and cancer. Biochim Biophys Acta. 2008;1786:60–72. doi:10.1016/j.bbcan.2008.07.003.
Ouchi M, Fujiuchi N, Sasai K, et al. BRCA1 phosphorylation by Aurora-A in the regulation of G2 to M transition. J Biol Chem. 2004;279:19643–8. doi:10.1074/jbc.M311780200.
Liu Q, Kaneko S, Yang L, et al. Aurora-A abrogation of p53 DNA binding and transactivation activity by phosphorylation of serine 215. J Biol Chem. 2004;279:52175–82. doi:10.1074/jbc.M406802200.
Gustafson WC, Meyerowitz JG, Nekritz EA, et al. Drugging MYCN through an allosteric transition in Aurora Kinase A. Cancer Cell. 2014;26:414–27. doi:10.1016/j.ccr.2014.07.015.
Sun C, Chan F, Briassouli P, Linardopoulos S. Aurora kinase inhibition downregulates NF-kB and sensitises tumour cells to chemotherapeutic agents. Biochem Biophys Res Commun. 2007;352:220–5. doi:10.1016/j.bbrc.2006.11.004.
Dutta-Simmons J, Zhang Y, Gorgun G, et al. Aurora kinase A is a target of Wnt/beta-catenin involved in multiple myeloma disease progression. Blood. 2009;114:2699–708. doi:10.1182/blood-2008-12-194290.
Wang X, Zhou Y-X, Qiao W, et al. Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation. Oncogene. 2006;25:7148–58. doi:10.1038/sj.onc.1209707.
Farruggio DC, Townsley FM, Ruderman JV. Cdc20 associates with the kinase aurora2/Aik. Proc Natl Acad Sci U S A. 1999;96:7306–11. doi:10.1073/pnas.96.13.7306.
Lehman NL, O’Donnell JP, Whiteley LJ, et al. Aurora A is differentially expressed in gliomas, is associated with patient survival in glioblastoma, and is a potential chemotherapeutic target in gliomas. Cell Cycle. 2012;11:489–502. doi:10.4161/cc.11.3.18996.
Samaras V, Stamatelli A, Samaras E, et al. Comparative immunohistochemical analysis of aurora-A and aurora-B expression in human glioblastomas. Associations with proliferative activity and clinicopathological features. Pathol Res Pract. 2009;205:765–73. doi:10.1016/j.prp.2009.06.011.
Klein A, Reichardt W, Jung V, Zang KD, Meese E, Urbschat S. Overexpression and amplification of STK15 in human gliomas. Int J Oncol. 2004;25:1789–94. doi:10.3892/ijo.25.6.1789.
Loh J-K, Lieu A-S, Chou C-H, et al. Differential expression of centrosomal proteins at different stages of human glioma. BMC Cancer. 2010;10:268. doi:10.1186/1471-2407-10-268.
Hong X, O’Donnell JP, Salazar CR, et al. The selective Aurora-A kinase inhibitor MLN8237 (alisertib) potently inhibits proliferation of glioblastoma neurosphere tumor stem-like cells and potentiates the effects of temozolomide and ionizing radiation. Cancer Chemother Pharmacol. 2014;73:983–90. doi:10.1007/s00280-014-2430-z.
Li N, Maly DJ, Chanthery YH, et al. Radiotherapy followed by Aurora Kinase inhibition targets tumor-propagating cells in human glioblastoma. Mol Cancer Ther. 2015;14:419–28. doi:10.1158/1535-7163.MCT-14-0526.
Yamashita YM, Mahowald AP, Perlin JR, Fuller MT. Asymmetric inheritance of mother versus daughter centrosome in stem cell division. Science. 2007;315:518–21. doi:10.1126/science.1134910.
Knoblich JA. Asymmetric cell division: recent developments and their implications for tumour biology. Nat Rev Mol Cell Biol. 2010;11:849–60. doi:10.1038/nrm3010.
Lee CY, Andersen RO, Cabernard C, et al. Drosophila Aurora-A kinase inhibits neuroblast self-renewal by regulating aPKC/Numb cortical polarity and spindle orientation. Genes Dev. 2006;20:3464–74. doi:10.1101/gad.1489406.
Johnston CA, Hirono K, Prehoda KE, Doe CQ. Building cortical polarity in a cell line: identification of an Aurora-A/PinsLINKER spindle orientation pathway. Cell. 2009;138:1150–63. doi:10.1016/j.cell.2009.07.041.
Wang H, Ouyang Y, Somers WG, et al. Polo inhibits progenitor self-renewal and regulates Numb asymmetry by phosphorylating Pon. Nature. 2007;449:96–100. doi:10.1038/nature06056.
Wirtz-Peitz F, Nishimura T, Knoblich JA. Linking cell cycle to asymmetric division: Aurora-A phosphorylates the par complex to regulate numb localization. Cell. 2008;135:161–73. doi:10.1016/j.cell.2008.07.049.
Wang H, Somers GW, Bashirullah A, et al. Aurora-A acts as a tumor suppressor and regulates self-renewal of Drosophila neuroblasts. Genes Dev. 2006;20:3453–63. doi:10.1101/gad.1487506.
Castellanos E, Dominguez P, Gonzalez C. Centrosome dysfunction in drosophila neural stem cells causes tumors that are not due to genome instability. Curr Biol. 2008;18:1209–14. doi:10.1016/j.cub.2008.07.029.
Wu M, Kwon HY, Rattis F, et al. Imaging hematopoietic precursor division in real time. Cell Stem Cell. 2007;1:541–54. doi:10.1016/j.stem.2007.08.009.
Cicalese A, Bonizzi G, Pasi CE, et al. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell. 2016;138:1083–95. doi:10.1016/j.cell.2009.06.048.
Sugiarto S, Persson AI, Munoz EG, et al. Asymmetry-defective oligodendrocyte progenitors are glioma precursors. Cancer Cell. 2011;20:328–40. doi:10.1016/j.ccr.2011.08.011.
Wang J, Zhu HH, Chu M, et al. Symmetrical and asymmetrical division analysis provides evidence for a hierarchy of prostate epithelial cell lineages. Nat Commun. 2014;28:4758. doi:10.1038/ncomms5758.
Lathia JD, Hitomi M, Gallagher J, et al. Distribution of CD133 reveals glioma stem cells self-renew through symmetric and asymmetric cell divisions. Cell Death Dis. 2011;2:e200. doi:10.1038/cddis.2011.80.
Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8:755–68. doi:10.1038/nrc2499.
Micalizzi DS, Farabaugh SM, Ford HL. Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia. 2010;15:117–34. doi:10.1007/s10911-010-9178-9.
Davies J. Mesenchyme to epithelium transition during development of the mammalian kidney tubule. Acta Anat. 1996;156:187–201.
Cheng GZ, Chan J, Wang Q, et al. Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res. 2007;67:1979–87. doi:10.1158/0008-5472.CAN-06-1479.
Comijn J, Berx G, Vermassen P, et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-Cadherin and induces invasion. Mol Cell. 2016;7:1267–78. doi:10.1016/S1097-2765(01)00260-X.
Hartwell KA, Muir B, Reinhardt F, et al. The Spemann organizer gene, Goosecoid, promotes tumor metastasis. Proc Natl Acad Sci U S A. 2006;103:18969–74. doi:10.1073/pnas.0608636103.
Oft M, Akhurst RJ, Balmain A. Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat Cell Biol. 2002;487–94. doi:10.1038/ncb807.
Mani SA, Yang J, Brooks M, et al. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc Natl Acad Sci U S A. 2007;104:10069–74. doi:10.1073/pnas.0703900104.
Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7:415–28. doi:10.1038/nrc2131.
Morel A-P, Lièvre M, Thomas C, et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One. 2008;3:e2888. doi:10.1371/journal.pone.0002888.
Mani SA, Guo W, Liao M, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15. doi:10.1016/j.cell.2008.03.027.
Camand E, Peglion F, Osmani N, et al. N-cadherin expression level modulates integrin-mediated polarity and strongly impacts on the speed and directionality of glial cell migration. J Cell Sci. 2012;125:844–57. doi:10.1242/jcs.087668.
Duenisch P, Reichart R, Mueller U, et al. Neural cell adhesion molecule isoform 140 declines with rise of WHO grade in human gliomas and serves as indicator for the invasion zone of multiform glioblastomas and brain metastases. J Cancer Res Clin Oncol. 2010;137:399–414. doi:10.1007/s00432-010-0888-6.
Amoureux M-C, Coulibaly B, Chinot O, et al. Polysialic acid neural cell adhesion molecule (PSA-NCAM) is an adverse prognosis factor in glioblastoma, and regulates olig2 expression in glioma cell lines. BMC Cancer. 2010;10:1–12. doi:10.1186/1471-2407-10-91.
Joseph JV, Conroy S, Pavlov K, et al. Hypoxia enhances migration and invasion in glioblastoma by promoting a mesenchymal shift mediated by the HIF1α–ZEB1 axis. Cancer Lett. 2015;359:107–16. doi:10.1016/j.canlet.2015.01.010.
Elias MC, Tozer KR, Silber JR, et al. TWIST is expressed in human gliomas and promotes invasion. Neoplasia. 2005;7:824–37.
Motta FJN, Valera ET, Lucio-Eterovic AKB, et al. Differential expression of E-cadherin gene in human neuroepithelial tumors. Genet Mol Res. 2008;7:295–304. doi:10.4238/vol7-2gmr424.
Han S-P, Kim J-H, Han M-E, et al. SNAI1 is involved in the proliferation and migration of glioblastoma cells. Cell Mol Neurobiol. 2011;31:489–96. doi:10.1007/s10571-010-9643-4.
Verhaak GH, Hoadley C, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. An integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR and NF1. Cancer. 2010;19:38–46. doi:10.1016/j.ccr.2009.12.020.An.
Sturm D, Bender S, Jones DTW, et al. Paediatric and adult glioblastoma: multiform (epi)genomic Culprits Emerge. Nat Rev Cancer. 2014;14:92–107. doi:10.1038/nrc3655.Paediatric.
Phillips HS, Kharbanda S, Chen R, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9:157–73. doi:10.1016/j.ccr.2006.02.019.
Tso C-L, Shintaku P, Chen J, et al. Primary glioblastomas express mesenchymal stem-like properties. Mol Cancer Res. 2006;4:607–19. doi:10.1158/1541-7786.MCR-06-0005.
Kahlert UD, Suwala A, Raabe EH, et al. Zeb1 promotes invasion in human fetal neural stem cells and hypoxic glioma neurospheres. Brain Pathol. 2015;25:724–32. doi:10.1111/bpa.12240.
Bhat KPL, Balasubramaniyan V, Vaillant B, et al. Mesenchymal differentiation mediated by NFkB promotes radiation resistance in glioblastoma. Cancer Cell. 2016;24:331–46. doi:10.1016/j.ccr.2013.08.001.
Goffart N, Lombard A, Lallemand F, et al. CXCL12 mediates Glioblastoma Resistance to Radiotherapy in the Subventricular Zone. Neurol Oncol. 2016;1–11. doi:10.1093/neuonc/now136.
Lombard A, Goffart N, Rogister B. Glioblastoma circulating cells: reality, trap or illusion? Stem Cells Int. 2015;2015:1–11. doi:10.1155/2015/182985.
Lorenzo C, Liao Q, Hardwicke MA, Ducommun B. Pharmacological inhibition of aurora-A but not aurora-B impairs interphase microtubule dynamics. Cell Cycle. 2009;8:1733–7. doi:10.4161/cc.8.11.8617.
Mori D, Yamada M, Mimori-Kiyosue Y, et al. An essential role of the aPKC-Aurora A-NDEL1 pathway in neurite elongation by modulation of microtubule dynamics. Nat Cell Biol. 2009;11:1057–68. doi:10.1038/ncb1919.
Vogelmann R, Nelson WJ. Fractionation of the epithelial apical junctional complex: reassessment of protein distributions in different substructures. Mol Biol Cell. 2005;16:701–16. doi:10.1091/mbc.E04-09-0827.
Royer C, Lu X. Epithelial cell polarity: a major gatekeeper against cancer? Cell Death Differ. 2011;18:1470–7. doi:10.1038/cdd.2011.60.
D’Assoro AB, Liu T, Quatraro C, et al. The mitotic kinase Aurora-A promotes distant metastases by inducing epithelial-to-mesenchymal transition in ERα(+) breast cancer cells. Oncogene. 2014;33:599–610. doi:10.1038/onc.2012.628.
Wang L, Xiang J, Yan M, et al. The mitotic kinase Aurora-A induces mammary cell migration and breast cancer metastasis by activating the Cofilin-F-actin pathway. Cancer Res. 2010;70:9118–28. doi:10.1158/0008-5472.CAN-10-1246.
Wan XB, Long ZJ, Yan M, et al. Inhibition of Aurora-A suppresses epithelial-mesenchymal transition and invasion by downregulating MAPK in nasopharyngeal carcinoma cells. Carcinogenesis. 2008;29:1930–7. doi:10.1093/carcin/bgn176.
Chou CH, Yang NK, Liu TY, et al. Chromosome instability modulated by BMI1-AURKA signaling drives progression in head and neck cancer. Cancer Res. 2013;73:953–66. doi:10.1158/0008-5472.CAN-12-2397.
Batlle E, Sancho E, Franci C, et al. The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000;2:84–9. doi:10.1038/35000034.
Wang X, Lu N, Niu B, et al. Overexpression of Aurora-A enhances invasion and matrix metalloproteinase-2 expression in esophageal squamous cell carcinoma cells. Mol Cancer Res. 2012;10:588–96. doi:10.1158/1541-7786.MCR-11-0416.
Cammareri P, Scopelliti A, Todaro M, et al. Aurora-a is essential for the tumorigenic capacity and chemoresistance of colorectal cancer stem cells. Cancer Res. 2010;70:4655–65. doi:10.1158/0008-5472.CAN-09-3953.
Mannino M, Gomez-Roman N, Hochegger H, Chalmers AJ. Differential sensitivity of Glioma stem cells to Aurora kinase A inhibitors: implications for stem cell mitosis and centrosome dynamics. Stem Cell Res. 2014;13:135–43. doi:10.1016/j.scr.2014.05.001.
Van Brocklyn JR, Wojton J, Meisen WH, et al. Aurora-A inhibition offers a novel therapy effective against intracranial glioblastoma. Cancer Res. 2014;74:5364–70. doi:10.1158/0008-5472.CAN-14-0386.
De Bacco F, D’Ambrosio A, Casanova E, et al. MET inhibition overcomes radiation resistance of glioblastoma stem-like cells. EMBO Mol Med. 2016;8:1–19. doi:10.15252/emmm.201505890.
Boccaccio C, Comoglio PM. MET, a driver of invasive growth and cancer clonal evolution under therapeutic pressure. Curr Opin Cell Biol. 2014;31:98–105. doi:10.1016/j.ceb.2014.09.008.
Li Y, Li A, Glas M, et al. c-Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype. Proc Natl Acad Sci U S A. 2011;108:9951–6. doi:10.1073/pnas.1016912108.
Niu H, Manfredi M, Ecsedy JA. Scientific rationale supporting the clinical development strategy for the investigational Aurora A Kinase inhibitor alisertib in cancer. Front Oncol. 2015;5:189. doi:10.3389/fonc.2015.00189.
Falchook GS, Bastida CC, Kurzrock R. Aurora kinase inhibitors in oncology clinical trials: current state of the progress. Semin Oncol. 2015;42:832–48. doi:10.1053/j.seminoncol.2015.09.022.
Fletcher GC, Brokx RD, Denny TA, et al. ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action. Am Assoc Cancer Res. 2011;10:126–37. doi:10.1158/1535-7163.MCT-10-0574.
Matulonis UA, Lee J, Lasonde B, et al. ENMD-2076, an oral inhibitor of angiogenic and proliferation kinases, has activity in recurrent, platinum resistant ovarian cancer. Eur J Cancer. 2016;49:121–31. doi:10.1016/j.ejca.2012.07.020.
Manfredi MG, Ecsedy JA, Chakravarty A, et al. Characterization of alisertib (MLN8237), an investigational small-molecule inhibitor of Aurora A kinase using novel in vivo pharmacodynamic assays. Clin Cancer Res. 2011;17:7614–24. doi:10.1158/1078-0432.CCR-11-1536.