1932

Abstract

Aneuploidy is a hallmark of cancer. Defects in chromosome segregation result in aneuploidy. Multiple pathways are engaged in this process, including errors in kinetochore-microtubule attachments, supernumerary centrosomes, spindle assembly checkpoint (SAC) defects, and chromosome cohesion defects. Although aneuploidy provides an adaptation and proliferative advantage in affected cells, excessive aneuploidy beyond a critical level can be lethal to cancer cells. Given this, enhanced chromosome missegregation is hypothesized to limit survival of aneuploid cancer cells, especially when compared to diploid cells. Based on this concept, proteins and pathways engaged in chromosome segregation are being exploited as candidate therapeutic targets for aneuploid cancers. Agents that induce chromosome missegregation and aneuploidy now exist, including SAC inhibitors, those that alter centrosome fidelity and others that are under active study in preclinical and clinical contexts. This review explores the therapeutic potentials of such new agents, including the benefits of combining them with other antineoplastic agents.

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2019-01-06
2024-06-20
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Literature Cited

  1. 1.  Hanahan D, Weinberg RA 2011. Hallmarks of cancer: the next generation. Cell 144:646–74
    [Google Scholar]
  2. 2.  Lengauer C, Kinzler KW, Vogelstein B 1997. Genetic instability in colorectal cancers. Nature 386:623–27
    [Google Scholar]
  3. 3.  Duijf PH, Benezra R 2013. The cancer biology of whole-chromosome instability. Oncogene 32:4727–36
    [Google Scholar]
  4. 4.  Giam M, Rancati G 2015. Aneuploidy and chromosomal instability in cancer: a jackpot to chaos. Cell Div 10:3
    [Google Scholar]
  5. 5.  Rajagopalan H, Lengauer C 2004. Aneuploidy and cancer. Nature 432:338–41
    [Google Scholar]
  6. 6.  Thompson SL, Compton DA 2008. Examining the link between chromosomal instability and aneuploidy in human cells. J. Cell Biol. 180:665–72
    [Google Scholar]
  7. 7.  Kops GJ, Weaver BA, Cleveland DW 2005. On the road to cancer: aneuploidy and the mitotic checkpoint. Nat. Rev. Cancer 5:773–85
    [Google Scholar]
  8. 8.  Ozery-Flato M, Linhart C, Trakhtenbrot L, Izraeli S, Shamir R 2011. Large-scale analysis of chromosomal aberrations in cancer karyotypes reveals two distinct paths to aneuploidy. Genome Biol 12:R61
    [Google Scholar]
  9. 9.  Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S et al. 2010. The landscape of somatic copy-number alteration across human cancers. Nature 463:899–905
    [Google Scholar]
  10. 10.  Cimini D 2008. Merotelic kinetochore orientation, aneuploidy, and cancer. Biochim. Biophys. Acta 1786:32–40
    [Google Scholar]
  11. 11.  Bakhoum SF, Compton DA 2012. Chromosomal instability and cancer: a complex relationship with therapeutic potential. J. Clin. Investig. 122:1138–43
    [Google Scholar]
  12. 12.  Orr B, Godek KM, Compton D 2015. Aneuploidy. Curr. Biol. 25:R538–42
    [Google Scholar]
  13. 13.  Gao C, Furge K, Koeman J, Dykema K, Su Y et al. 2007. Chromosome instability, chromosome transcriptome, and clonal evolution of tumor cell populations. PNAS 104:8995–9000
    [Google Scholar]
  14. 14.  Sawyers CL 2001. Research on resistance to cancer drug Gleevec. Science 294:1834
    [Google Scholar]
  15. 15.  Wang TL, Diaz LA Jr, Romans K, Bardelli A, Saha S et al. 2004. Digital karyotyping identifies thymidyl-ate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. PNAS 101:3089–94
    [Google Scholar]
  16. 16.  Watanabe T, Wu TT, Catalano PJ, Ueki T, Satriano R et al. 2001. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N. Engl. J. Med. 344:1196–206
    [Google Scholar]
  17. 17.  Zhou W, Goodman SN, Galizia G, Lieto E, Ferraraccio F et al. 2002. Counting alleles to predict recurrence of early-stage colorectal cancers. Lancet 359:219–25
    [Google Scholar]
  18. 18.  Risques RA, Moreno V, Ribas M, Marcuello E, Capella G, Peinado MA 2003. Genetic pathways and genome-wide determinants of clinical outcome in colorectal cancer. Cancer Res 63:7206–14
    [Google Scholar]
  19. 19.  Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C et al. 1998. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. Blood 92:2322–33
    [Google Scholar]
  20. 20.  Gulley ML, Shea TC, Fedoriw Y 2010. Genetic tests to evaluate prognosis and predict therapeutic response in acute myeloid leukemia. J. Mol. Diagn. 12:3–16
    [Google Scholar]
  21. 21.  McGranahan N, Burrell RA, Endesfelder D, Novelli MR, Swanton C 2012. Cancer chromosomal instability: therapeutic and diagnostic challenges. EMBO Rep 13:528–38
    [Google Scholar]
  22. 22.  Bakhoum SF, Danilova OV, Kaur P, Levy NB, Compton DA 2011. Chromosomal instability substantiates poor prognosis in patients with diffuse large B-cell lymphoma. Clin. Cancer Res. 17:7704–11
    [Google Scholar]
  23. 23.  Thompson SL, Bakhoum SF, Compton DA 2010. Mechanisms of chromosomal instability. Curr. Biol. 20:R285–95
    [Google Scholar]
  24. 24.  Gordon DJ, Resio B, Pellman D 2012. Causes and consequences of aneuploidy in cancer. Nat. Rev. Genet. 13:189–203
    [Google Scholar]
  25. 25.  Bakhoum SF, Thompson SL, Manning AL, Compton DA 2009. Genome stability is ensured by temporal control of kinetochore-microtubule dynamics. Nat. Cell Biol. 11:27–35
    [Google Scholar]
  26. 26.  Bakhoum SF, Genovese G, Compton DA 2009. Deviant kinetochore microtubule dynamics underlie chromosomal instability. Curr. Biol. 19:1937–42
    [Google Scholar]
  27. 27.  Lentini L, Amato A, Schillaci T, Di Leonardo A 2007. Simultaneous Aurora-A/STK15 overexpression and centrosome amplification induce chromosomal instability in tumour cells with a MIN phenotype. BMC Cancer 7:212
    [Google Scholar]
  28. 28.  Silkworth WT, Nardi IK, Scholl LM, Cimini D 2009. Multipolar spindle pole coalescence is a major source of kinetochore mis-attachment and chromosome mis-segregation in cancer cells. PLOS ONE 4:e6564
    [Google Scholar]
  29. 29.  Ganem NJ, Godinho SA, Pellman D 2009. A mechanism linking extra centrosomes to chromosomal instability. Nature 460:278–82
    [Google Scholar]
  30. 30.  Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK et al. 1998. Mutations of mitotic checkpoint genes in human cancers. Nature 392:300–3
    [Google Scholar]
  31. 31.  Sotillo R, Schvartzman JM, Socci ND, Benezra R 2010. Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature 464:436–40
    [Google Scholar]
  32. 32.  Diaz-Rodriguez E, Sotillo R, Schvartzman JM, Benezra R 2008. Hec1 overexpression hyperactivates the mitotic checkpoint and induces tumor formation in vivo. PNAS 105:16719–24
    [Google Scholar]
  33. 33.  Zhang N, Ge G, Meyer R, Sethi S, Basu D et al. 2008. Overexpression of separase induces aneuploidy and mammary tumorigenesis. PNAS 105:13033–38
    [Google Scholar]
  34. 34.  Nicklas RB, Ward SC 1994. Elements of error correction in mitosis: microtubule capture, release, and tension. J. Cell Biol. 126:1241–53
    [Google Scholar]
  35. 35.  Cimini D, Howell B, Maddox P, Khodjakov A, Degrassi F, Salmon ED 2001. Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells. J. Cell Biol. 153:517–27
    [Google Scholar]
  36. 36.  Compton DA 2011. Mechanisms of aneuploidy. Curr. Opin. Cell Biol. 23:109–13
    [Google Scholar]
  37. 37.  Gregan J, Polakova S, Zhang L, Tolic-Norrelykke IM, Cimini D 2011. Merotelic kinetochore attachment: causes and effects. Trends Cell Biol 21:374–81
    [Google Scholar]
  38. 38.  Bornens M 2002. Centrosome composition and microtubule anchoring mechanisms. Curr. Opin. Cell Biol. 14:25–34
    [Google Scholar]
  39. 39.  Bettencourt-Dias M, Glover DM 2007. Centrosome biogenesis and function: Centrosomics brings new understanding. Nat. Rev. Mol. Cell Biol. 8:451–63
    [Google Scholar]
  40. 40.  Brito DA, Gouveia SM, Bettencourt-Dias M 2012. Deconstructing the centriole: structure and number control. Curr. Opin. Cell Biol. 24:4–13
    [Google Scholar]
  41. 41.  Firat-Karalar EN, Stearns T 2014. The centriole duplication cycle. Philos. Trans. R. Soc. Lond. B Biol. Sci. 369:20130460
    [Google Scholar]
  42. 42.  Hinchcliffe EH, Sluder G 2001. “It takes two to tango”: understanding how centrosome duplication is regulated throughout the cell cycle. Genes Dev 15:1167–81
    [Google Scholar]
  43. 43.  Kramer A, Neben K, Ho AD 2002. Centrosome replication, genomic instability and cancer. Leukemia 16:767–75
    [Google Scholar]
  44. 44.  Zyss D, Gergely F 2009. Centrosome function in cancer: guilty or innocent?. Trends Cell Biol 19:334–46
    [Google Scholar]
  45. 45.  Chan JY 2011. A clinical overview of centrosome amplification in human cancers. Int. J. Biol. Sci. 7:1122–44
    [Google Scholar]
  46. 46.  Nigg EA 2002. Centrosome aberrations: cause or consequence of cancer progression?. Nat. Rev. Cancer 2:815–25
    [Google Scholar]
  47. 47.  Lingle WL, Salisbury JL 1999. Altered centrosome structure is associated with abnormal mitoses in human breast tumors. Am. J. Pathol. 155:1941–51
    [Google Scholar]
  48. 48.  Pihan GA, Wallace J, Zhou Y, Doxsey SJ 2003. Centrosome abnormalities and chromosome instability occur together in pre-invasive carcinomas. Cancer Res 63:1398–404
    [Google Scholar]
  49. 49.  Lingle WL, Lutz WH, Ingle JN, Maihle NJ, Salisbury JL 1998. Centrosome hypertrophy in human breast tumors: implications for genomic stability and cell polarity. PNAS 95:2950–55
    [Google Scholar]
  50. 50.  Pihan GA, Purohit A, Wallace J, Knecht H, Woda B et al. 1998. Centrosome defects and genetic instability in malignant tumors. Cancer Res 58:3974–85
    [Google Scholar]
  51. 51.  Musacchio A, Salmon ED 2007. The spindle-assembly checkpoint in space and time. Nat. Rev. Mol. Cell Biol. 8:379–93
    [Google Scholar]
  52. 52.  Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C 2003. The significance of unstable chromosomes in colorectal cancer. Nat. Rev. Cancer 3:695–701
    [Google Scholar]
  53. 53.  Dominguez-Brauer C, Thu KL, Mason JM, Blaser H, Bray MR, Mak TW 2015. Targeting mitosis in cancer: emerging strategies. Mol. Cell 60:524–36
    [Google Scholar]
  54. 54.  Park HY, Jeon YK, Shin HJ, Kim IJ, Kang HC et al. 2007. Differential promoter methylation may be a key molecular mechanism in regulating BubR1 expression in cancer cells. Exp. Mol. Med. 39:195–204
    [Google Scholar]
  55. 55.  Haruta M, Matsumoto Y, Izumi H, Watanabe N, Fukuzawa M et al. 2008. Combined BubR1 protein down-regulation and RASSF1A hypermethylation in Wilms tumors with diverse cytogenetic changes. Mol. Carcinog. 47:660–66
    [Google Scholar]
  56. 56.  Peters JM, Tedeschi A, Schmitz J 2008. The cohesin complex and its roles in chromosome biology. Genes Dev 22:3089–114
    [Google Scholar]
  57. 57.  Barber TD, McManus K, Yuen KW, Reis M, Parmigiani G et al. 2008. Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers. PNAS 105:3443–48
    [Google Scholar]
  58. 58.  Iwaizumi M, Shinmura K, Mori H, Yamada H, Suzuki M et al. 2009. Human Sgo1 downregulation leads to chromosomal instability in colorectal cancer. Gut 58:249–60
    [Google Scholar]
  59. 59.  Solomon DA, Kim T, Diaz-Martinez LA, Fair J, Elkahloun AG et al. 2011. Mutational inactivation of STAG2 causes aneuploidy in human cancer. Science 333:1039–43
    [Google Scholar]
  60. 60.  Janssen A, Kops GJ, Medema RH 2009. Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cells. PNAS 106:19108–13
    [Google Scholar]
  61. 61.  Komarova NL, Wodarz D 2004. The optimal rate of chromosome loss for the inactivation of tumor suppressor genes in cancer. PNAS 101:7017–21
    [Google Scholar]
  62. 62.  Birkbak NJ, Eklund AC, Li Q, McClelland SE, Endesfelder D et al. 2011. Paradoxical relationship between chromosomal instability and survival outcome in cancer. Cancer Res 71:3447–52
    [Google Scholar]
  63. 63.  Roylance R, Endesfelder D, Gorman P, Burrell RA, Sander J et al. 2011. Relationship of extreme chromosomal instability with long-term survival in a retrospective analysis of primary breast cancer. Cancer Epidemiol. Biomarkers Prev. 20:2183–94
    [Google Scholar]
  64. 64.  Kops GJ, Foltz DR, Cleveland DW 2004. Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint. PNAS 101:8699–704
    [Google Scholar]
  65. 65.  Stolz A, Vogel C, Schneider V, Ertych N, Kienitz A et al. 2009. Pharmacologic abrogation of the mitotic spindle checkpoint by an indolocarbazole discovered by cellular screening efficiently kills cancer cells. Cancer Res 69:3874–83
    [Google Scholar]
  66. 66.  Kwiatkowski N, Jelluma N, Filippakopoulos P, Soundararajan M, Manak MS et al. 2010. Small-molecule kinase inhibitors provide insight into Mps1 cell cycle function. Nat. Chem. Biol. 6:359–68
    [Google Scholar]
  67. 67.  Abrieu A, Magnaghi-Jaulin L, Kahana JA, Peter M, Castro A et al. 2001. Mps1 is a kinetochore-associated kinase essential for the vertebrate mitotic checkpoint. Cell 106:83–93
    [Google Scholar]
  68. 68.  Yuan B, Xu Y, Woo JH, Wang Y, Bae YK et al. 2006. Increased expression of mitotic checkpoint genes in breast cancer cells with chromosomal instability. Clin. Cancer Res. 12:405–10
    [Google Scholar]
  69. 69.  Daniel J, Coulter J, Woo JH, Wilsbach K, Gabrielson E 2011. High levels of the Mps1 checkpoint protein are protective of aneuploidy in breast cancer cells. PNAS 108:5384–89
    [Google Scholar]
  70. 70.  Tannous BA, Kerami M, Van der Stoop PM, Kwiatkowski N, Wang J et al. 2013. Effects of the selective MPS1 inhibitor MPS1-IN-3 on glioblastoma sensitivity to antimitotic drugs. J. Natl. Cancer Inst. 105:1322–31
    [Google Scholar]
  71. 71.  Colombo R, Caldarelli M, Mennecozzi M, Giorgini ML, Sola F et al. 2010. Targeting the mitotic checkpoint for cancer therapy with NMS-P715, an inhibitor of MPS1 kinase. Cancer Res 70:10255–64
    [Google Scholar]
  72. 72.  Jemaa M, Galluzzi L, Kepp O, Senovilla L, Brands M et al. 2013. Characterization of novel MPS1 inhibitors with preclinical anticancer activity. Cell Death Differ 20:1532–45
    [Google Scholar]
  73. 73.  Tardif KD, Rogers A, Cassiano J, Roth BL, Cimbora DM et al. 2011. Characterization of the cellular and antitumor effects of MPI-0479605, a small-molecule inhibitor of the mitotic kinase Mps1. Mol. Cancer Ther. 10:2267–75
    [Google Scholar]
  74. 74.  Lan W, Cleveland DW 2010. A chemical tool box defines mitotic and interphase roles for Mps1 kinase. J. Cell Biol. 190:21–24
    [Google Scholar]
  75. 75.  Liu X, Winey M 2012. The MPS1 family of protein kinases. Annu. Rev. Biochem. 81:561–85
    [Google Scholar]
  76. 76.  Mason JM, Wei X, Fletcher GC, Kiarash R, Brokx R et al. 2017. Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer. PNAS 114:3127–32
    [Google Scholar]
  77. 77.  Meraldi P, Sorger PK 2005. A dual role for Bub1 in the spindle checkpoint and chromosome congression. EMBO J 24:1621–33
    [Google Scholar]
  78. 78.  Bettencourt-Dias M, Rodrigues-Martins A, Carpenter L, Riparbelli M, Lehmann L et al. 2005. SAK/PLK4 is required for centriole duplication and flagella development. Curr. Biol. 15:2199–207
    [Google Scholar]
  79. 79.  Habedanck R, Stierhof YD, Wilkinson CJ, Nigg EA 2005. The Polo kinase Plk4 functions in centriole duplication. Nat. Cell Biol. 7:1140–46
    [Google Scholar]
  80. 80.  van de Vijver MJ, He YD, van't Veer LJ, Dai H, Hart AA et al. 2002. A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 347:1999–2009
    [Google Scholar]
  81. 81.  Miller LD, Smeds J, George J, Vega VB, Vergara L et al. 2005. An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. PNAS 102:13550–55
    [Google Scholar]
  82. 82.  Pezuk JA, Brassesco MS, de Oliveira RS, Machado HR, Neder L et al. 2017. PLK1-associated microRNAs are correlated with pediatric medulloblastoma prognosis. Childs Nerv. Syst. 33:609–15
    [Google Scholar]
  83. 83.  Sredni ST, Tomita T 2017. The polo-like kinase 4 gene (PLK4) is overexpressed in pediatric medulloblastoma. Childs Nerv. Syst. 33:1031
    [Google Scholar]
  84. 84.  Kawakami M, Mustachio LM, Zheng L, Chen Y, Rodriguez-Canales J et al. 2018. Polo-like kinase 4 inhibition produces polyploidy and apoptotic death of lung cancers. PNAS 115:1913–18
    [Google Scholar]
  85. 85.  Kleylein-Sohn J, Westendorf J, Le Clech M, Habedanck R, Stierhof YD, Nigg EA 2007. Plk4-induced centriole biogenesis in human cells. Dev. Cell 13:190–202
    [Google Scholar]
  86. 86.  Peel N, Stevens NR, Basto R, Raff JW 2007. Overexpressing centriole-replication proteins in vivo induces centriole overduplication and de novo formation. Curr. Biol. 17:834–43
    [Google Scholar]
  87. 87.  Kwon M, Godinho SA, Chandhok NS, Ganem NJ, Azioune A et al. 2008. Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. Genes Dev 22:2189–203
    [Google Scholar]
  88. 88.  Mason JM, Lin DC, Wei X, Che Y, Yao Y et al. 2014. Functional characterization of CFI-400945, a Polo-like kinase 4 inhibitor, as a potential anticancer agent. Cancer Cell 26:163–76
    [Google Scholar]
  89. 89.  Wong YL, Anzola JV, Davis RL, Yoon M, Motamedi A et al. 2015. Reversible centriole depletion with an inhibitor of Polo-like kinase 4. Science 348:1155–60
    [Google Scholar]
  90. 90.  Sampson PB, Liu Y, Forrest B, Cumming G, Li SW et al. 2015. The discovery of Polo-like kinase 4 inhibitors: identification of (1R,2S)-2-(3-((E)-4-(((cis)-2,6-dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (CFI-400945) as a potent, orally active antitumor agent. J. Med. Chem. 58:147–69
    [Google Scholar]
  91. 91.  Ring D, Hubble R, Kirschner M 1982. Mitosis in a cell with multiple centrioles. J. Cell Biol. 94:549–56
    [Google Scholar]
  92. 92.  Quintyne NJ, Reing JE, Hoffelder DR, Gollin SM, Saunders WS 2005. Spindle multipolarity is prevented by centrosomal clustering. Science 307:127–29
    [Google Scholar]
  93. 93.  Brinkley BR 2001. Managing the centrosome numbers game: from chaos to stability in cancer cell division. Trends Cell Biol 11:18–21
    [Google Scholar]
  94. 94.  Godinho SA, Kwon M, Pellman D 2009. Centrosomes and cancer: how cancer cells divide with too many centrosomes. Cancer Metastasis Rev 28:85–98
    [Google Scholar]
  95. 95.  Leber B, Maier B, Fuchs F, Chi J, Riffel P et al. 2010. Proteins required for centrosome clustering in cancer cells. Sci. Transl. Med. 2:33ra38
    [Google Scholar]
  96. 96.  Fielding AB, Lim S, Montgomery K, Dobreva I, Dedhar S 2011. A critical role of integrin-linked kinase, ch-TOG and TACC3 in centrosome clustering in cancer cells. Oncogene 30:521–34
    [Google Scholar]
  97. 97.  Gentric G, Celton-Morizur S, Desdouets C 2012. Polyploidy and liver proliferation. Clin. Res. Hepatol. Gastroenterol. 36:29–34
    [Google Scholar]
  98. 98.  Gentric G, Desdouets C 2015. Liver polyploidy: Dr Jekyll or Mr Hide?. Oncotarget 6:8430–31
    [Google Scholar]
  99. 99.  Galimberti F, Thompson SL, Liu X, Li H, Memoli V et al. 2010. Targeting the cyclin E-Cdk-2 complex represses lung cancer growth by triggering anaphase catastrophe. Clin. Cancer Res. 16:109–20
    [Google Scholar]
  100. 100.  Galimberti F, Thompson SL, Ravi S, Compton DA, Dmitrovsky E 2011. Anaphase catastrophe is a target for cancer therapy. Clin. Cancer Res. 17:1218–22
    [Google Scholar]
  101. 101.  Hu S, Danilov AV, Godek K, Orr B, Tafe LJ et al. 2015. CDK2 inhibition causes anaphase catastrophe in lung cancer through the centrosomal protein CP110. Cancer Res 75:2029–38
    [Google Scholar]
  102. 102.  Danilov AV, Hu S, Orr B, Godek K, Mustachio LM et al. 2016. Dinaciclib induces anaphase catastrophe in lung cancer cells via inhibition of cyclin-dependent kinases 1 and 2. Mol. Cancer Ther. 15:2758–66
    [Google Scholar]
  103. 103.  Kawakami M, Mustachio LM, Rodriguez-Canales J, Mino B, Roszik J et al. 2017. Next-generation CDK2/9 inhibitors and anaphase catastrophe in lung cancer. J. Natl. Cancer Inst. 109:djw297
    [Google Scholar]
  104. 104.  McClue SJ, Blake D, Clarke R, Cowan A, Cummings L et al. 2002. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine). Int. J. Cancer 102:463–68
    [Google Scholar]
  105. 105.  Whittaker SR, Walton MI, Garrett MD, Workman P 2004. The cyclin-dependent kinase inhibitor CYC202 (R-roscovitine) inhibits retinoblastoma protein phosphorylation, causes loss of Cyclin D1, and activates the mitogen-activated protein kinase pathway. Cancer Res 64:262–72
    [Google Scholar]
  106. 106.  Fleming IN, Hogben M, Frame S, McClue SJ, Green SR 2008. Synergistic inhibition of ErbB signaling by combined treatment with seliciclib and ErbB-targeting agents. Clin. Cancer Res. 14:4326–35
    [Google Scholar]
  107. 107.  Mountain V, Simerly C, Howard L, Ando A, Schatten G, Compton DA 1999. The kinesin-related protein, HSET, opposes the activity of Eg5 and cross-links microtubules in the mammalian mitotic spindle. J. Cell Biol. 147:351–66
    [Google Scholar]
  108. 108.  Cai S, Weaver LN, Ems-McClung SC, Walczak CE 2009. Kinesin-14 family proteins HSET/XCTK2 control spindle length by cross-linking and sliding microtubules. Mol. Biol. Cell 20:1348–59
    [Google Scholar]
  109. 109.  Kleylein-Sohn J, Pollinger B, Ohmer M, Hofmann F, Nigg EA et al. 2012. Acentrosomal spindle organization renders cancer cells dependent on the kinesin HSET. J. Cell Sci. 125:5391–402
    [Google Scholar]
  110. 110.  Watts CA, Richards FM, Bender A, Bond PJ, Korb O et al. 2013. Design, synthesis, and biological evaluation of an allosteric inhibitor of HSET that targets cancer cells with supernumerary centrosomes. Chem. Biol. 20:1399–410
    [Google Scholar]
  111. 111.  Lydersen BK, Pettijohn DE 1980. Human-specific nuclear protein that associates with the polar region of the mitotic apparatus: distribution in a human/hamster hybrid cell. Cell 22:489–99
    [Google Scholar]
  112. 112.  Compton DA, Luo C 1995. Mutation of the predicted p34cdc2 phosphorylation sites in NuMA impair the assembly of the mitotic spindle and block mitosis. J. Cell Sci. 108:621–33
    [Google Scholar]
  113. 113.  Compton DA, Cleveland DW 1993. NuMA is required for the proper completion of mitosis. J. Cell Biol. 120:947–57
    [Google Scholar]
  114. 114.  Gaglio T, Saredi A, Compton DA 1995. NuMA is required for the organization of microtubules into aster-like mitotic arrays. J. Cell Biol. 131:693–708
    [Google Scholar]
  115. 115.  Gaglio T, Saredi A, Bingham JB, Hasbani MJ, Gill SR et al. 1996. Opposing motor activities are required for the organization of the mammalian mitotic spindle pole. J. Cell Biol. 135:399–414
    [Google Scholar]
  116. 116.  Merdes A, Ramyar K, Vechio JD, Cleveland DW 1996. A complex of NuMA and cytoplasmic dynein is essential for mitotic spindle assembly. Cell 87:447–58
    [Google Scholar]
  117. 117.  Rebacz B, Larsen TO, Clausen MH, Ronnest MH, Loffler H et al. 2007. Identification of griseofulvin as an inhibitor of centrosomal clustering in a phenotype-based screen. Cancer Res 67:6342–50
    [Google Scholar]
  118. 118.  Raab MS, Breitkreutz I, Anderhub S, Ronnest MH, Leber B et al. 2012. GF-15, a novel inhibitor of centrosomal clustering, suppresses tumor cell growth in vitro and in vivo. Cancer Res 72:5374–85
    [Google Scholar]
  119. 119.  Sloboda RD, Van Blaricom G, Creasey WA, Rosenbaum JL, Malawista SE 1982. Griseofulvin: association with tubulin and inhibition of in vitro microtubule assembly. Biochem. Biophys. Res. Commun. 105:882–88
    [Google Scholar]
  120. 120.  Chaudhuri AR, Luduena RF 1996. Griseofulvin: a novel interaction with bovine brain tubulin. Biochem. Pharmacol. 51:903–9
    [Google Scholar]
  121. 121.  Rathinasamy K, Jindal B, Asthana J, Singh P, Balaji PV, Panda D 2010. Griseofulvin stabilizes microtubule dynamics, activates p53 and inhibits the proliferation of MCF-7 cells synergistically with vinblastine. BMC Cancer 10:213
    [Google Scholar]
  122. 122.  Gull K, Trinci AP 1973. Griseofulvin inhibits fungal mitosis. Nature 244:292–94
    [Google Scholar]
  123. 123.  Loo DS 2006. Systemic antifungal agents: an update of established and new therapies. Adv. Dermatol. 22:101–24
    [Google Scholar]
  124. 124.  Fielding AB, Dobreva I, Dedhar S 2008. Beyond focal adhesions: Integrin-linked kinase associates with tubulin and regulates mitotic spindle organization. Cell Cycle 7:1899–906
    [Google Scholar]
  125. 125.  Fielding AB, Dobreva I, McDonald PC, Foster LJ, Dedhar S 2008. Integrin-linked kinase localizes to the centrosome and regulates mitotic spindle organization. J. Cell Biol. 180:681–89
    [Google Scholar]
  126. 126.  McDonald PC, Fielding AB, Dedhar S 2008. Integrin-linked kinase—essential roles in physiology and cancer biology. J. Cell Sci. 121:3121–32
    [Google Scholar]
  127. 127.  Kalra J, Warburton C, Fang K, Edwards L, Daynard T et al. 2009. QLT0267, a small molecule inhibitor targeting integrin-linked kinase (ILK), and docetaxel can combine to produce synergistic interactions linked to enhanced cytotoxicity, reductions in P-AKT levels, altered F-actin architecture and improved treatment outcomes in an orthotopic breast cancer model. Breast Cancer Res 11:R25
    [Google Scholar]
  128. 128.  Xu HZ, Huang Y, Wu YL, Zhao Y, Xiao WL et al. 2010. Pharicin A, a novel natural ent-kaurene diterpenoid, induces mitotic arrest and mitotic catastrophe of cancer cells by interfering with BubR1 function. Cell Cycle 9:2897–907
    [Google Scholar]
  129. 129.  Santaguida S, Tighe A, D'Alise AM, Taylor SS, Musacchio A 2010. Dissecting the role of MPS1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversine. J. Cell Biol. 190:73–87
    [Google Scholar]
  130. 130.  Kawamura E, Fielding AB, Kannan N, Balgi A, Eaves CJ et al. 2013. Identification of novel small molecule inhibitors of centrosome clustering in cancer cells. Oncotarget 4:1763–76
    [Google Scholar]
  131. 131.  Sakowicz R, Finer JT, Beraud C, Crompton A, Lewis E et al. 2004. Antitumor activity of a kinesin inhibitor. Cancer Res 64:3276–80
    [Google Scholar]
  132. 132.  Huszar D, Theoclitou ME, Skolnik J, Herbst R 2009. Kinesin motor proteins as targets for cancer therapy. Cancer Metastasis Rev 28:197–208
    [Google Scholar]
  133. 133.  Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL, Mitchison TJ 1999. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286:971–74
    [Google Scholar]
  134. 134.  Carter BZ, Mak DH, Woessner R, Gross S, Schober WD et al. 2009. Inhibition of KSP by ARRY-520 induces cell cycle block and cell death via the mitochondrial pathway in AML cells. Leukemia 23:1755–62
    [Google Scholar]
  135. 135.  Harrington EA, Bebbington D, Moore J, Rasmussen RK, Ajose-Adeogun AO et al. 2004. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat. Med. 10:262–67
    [Google Scholar]
  136. 136.  Agnese V, Bazan V, Fiorentino FP, Fanale D, Badalamenti G et al. 2007. The role of Aurora-A inhibitors in cancer therapy. Ann. Oncol. 18:Suppl. 6vi47–52
    [Google Scholar]
  137. 137.  Dar AA, Goff LW, Majid S, Berlin J, El-Rifai W 2010. Aurora kinase inhibitors—rising stars in cancer therapeutics?. Mol. Cancer Ther. 9:268–78
    [Google Scholar]
  138. 138.  Warner SL, Stephens BJ, Von Hoff DD 2008. Tubulin-associated proteins: Aurora and Polo-like kinases as therapeutic targets in cancer. Curr. Oncol. Rep. 10:122–29
    [Google Scholar]
  139. 139.  Carpinelli P, Moll J 2009. Is there a future for Aurora kinase inhibitors for anticancer therapy?. Curr. Opin. Drug Discov. Dev. 12:533–42
    [Google Scholar]
  140. 140.  Kaseda K, Crevel I, Hirose K, Cross RA 2008. Single-headed mode of kinesin-5. EMBO Rep 9:761–65
    [Google Scholar]
  141. 141.  Rello-Varona S, Vitale I, Kepp O, Senovilla L, Jemaa M et al. 2009. Preferential killing of tetraploid tumor cells by targeting the mitotic kinesin Eg5. Cell Cycle 8:1030–35
    [Google Scholar]
  142. 142.  Malumbres M 2011. Physiological relevance of cell cycle kinases. Physiol. Rev. 91:973–1007
    [Google Scholar]
  143. 143.  Lara-Gonzalez P, Westhorpe FG, Taylor SS 2012. The spindle assembly checkpoint. Curr. Biol. 22:R966–80
    [Google Scholar]
  144. 144.  Goldberg SL, Fenaux P, Craig MD, Gyan E, Lister J et al. 2014. An exploratory phase 2 study of investigational Aurora A kinase inhibitor alisertib (MLN8237) in acute myelogenous leukemia and myelodysplastic syndromes. Leuk. Res. Rep. 3:58–61
    [Google Scholar]
  145. 145.  O'Regan L, Blot J, Fry AM 2007. Mitotic regulation by NIMA-related kinases. Cell Div 2:25
    [Google Scholar]
  146. 146.  Chen Y, Riley DJ, Zheng L, Chen PL, Lee WH 2002. Phosphorylation of the mitotic regulator protein Hec1 by Nek2 kinase is essential for faithful chromosome segregation. J. Biol. Chem. 277:49408–16
    [Google Scholar]
  147. 147.  Lou Y, Yao J, Zereshki A, Dou Z, Ahmed K et al. 2004. NEK2A interacts with MAD1 and possibly functions as a novel integrator of the spindle checkpoint signaling. J. Biol. Chem. 279:20049–57
    [Google Scholar]
  148. 148.  Du J, Cai X, Yao J, Ding X, Wu Q et al. 2008. The mitotic checkpoint kinase NEK2A regulates kinetochore microtubule attachment stability. Oncogene 27:4107–14
    [Google Scholar]
  149. 149.  Wei R, Ngo B, Wu G, Lee WH 2011. Phosphorylation of the Ndc80 complex protein, HEC1, by Nek2 kinase modulates chromosome alignment and signaling of the spindle assembly checkpoint. Mol. Biol. Cell 22:3584–94
    [Google Scholar]
  150. 150.  Cappello P, Blaser H, Gorrini C, Lin DC, Elia AJ et al. 2014. Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells. Oncogene 33:2375–84
    [Google Scholar]
  151. 151.  Eto M, Elliott E, Prickett TD, Brautigan DL 2002. Inhibitor-2 regulates protein phosphatase-1 complexed with NimA-related kinase to induce centrosome separation. J. Biol. Chem. 277:44013–20
    [Google Scholar]
  152. 152.  Li M, Satinover DL, Brautigan DL 2007. Phosphorylation and functions of inhibitor-2 family of proteins. Biochemistry 46:2380–89
    [Google Scholar]
  153. 153.  Rellos P, Ivins FJ, Baxter JE, Pike A, Nott TJ et al. 2007. Structure and regulation of the human Nek2 centrosomal kinase. J. Biol. Chem. 282:6833–42
    [Google Scholar]
  154. 154.  Wu G, Qiu XL, Zhou L, Zhu J, Chamberlin R et al. 2008. Small molecule targeting the Hec1/Nek2 mitotic pathway suppresses tumor cell growth in culture and in animal. Cancer Res 68:8393–99
    [Google Scholar]
  155. 155.  Westwood I, Cheary DM, Baxter JE, Richards MW, van Montfort RL et al. 2009. Insights into the conformational variability and regulation of human Nek2 kinase. J. Mol. Biol. 386:476–85
    [Google Scholar]
  156. 156.  Meng L, Carpenter K, Mollard A, Vankayalapati H, Warner SL et al. 2014. Inhibition of Nek2 by small molecules affects proteasome activity. Biomed. Res. Int. 2014:273180
    [Google Scholar]
  157. 157.  Weiss L, Efferth T 2012. Polo-like kinase 1 as target for cancer therapy. Exp. Hematol. Oncol. 1:38
    [Google Scholar]
  158. 158.  Strebhardt K 2010. Multifaceted polo-like kinases: drug targets and antitargets for cancer therapy. Nat. Rev. Drug Discov. 9:643–60
    [Google Scholar]
  159. 159.  Torres EM, Sokolsky T, Tucker CM, Chan LY, Boselli M et al. 2007. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 317:916–24
    [Google Scholar]
  160. 160.  Tang YC, Williams BR, Siegel JJ, Amon A 2011. Identification of aneuploidy-selective antiproliferation compounds. Cell 144:499–512
    [Google Scholar]
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