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Cell cycle control in cancer

Nature Reviews Molecular Cell Biology volume 23, pages 74–88 (2022)Cite this article

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Abstract

Cancer is a group of diseases in which cells divide continuously and excessively. Cell division is tightly regulated by multiple evolutionarily conserved cell cycle control mechanisms, to ensure the production of two genetically identical cells. Cell cycle checkpoints operate as DNA surveillance mechanisms that prevent the accumulation and propagation of genetic errors during cell division. Checkpoints can delay cell cycle progression or, in response to irreparable DNA damage, induce cell cycle exit or cell death. Cancer-associated mutations that perturb cell cycle control allow continuous cell division chiefly by compromising the ability of cells to exit the cell cycle. Continuous rounds of division, however, create increased reliance on other cell cycle control mechanisms to prevent catastrophic levels of damage and maintain cell viability. New detailed insights into cell cycle control mechanisms and their role in cancer reveal how these dependencies can be best exploited in cancer treatment.

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Fig. 1: The cell division cycle.
Fig. 2: Checkpoint-dependent cell cycle arrest and exit.
Fig. 3: Key signalling pathways involved in cell cycle control and cancer.
Fig. 4: Cancer’s continued proliferation presents many therapeutic opportunities.

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References

  1. Kops, G. J. P. L., Foltz, D. R. & Cleveland, D. W. Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint. Proc. Natl Acad. Sci. USA 101, 8699–8704 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Pennycook, B. R. & Barr, A. R. Restriction point regulation at the crossroads between quiescence and cell proliferation. FEBS Lett. 54, 2046–2060 (2020).

    Google Scholar 

  3. Rubin, S. M., Sage, J. & Skotheim, J. M. Integrating old and new paradigms of G1/S control. Mol. Cell 80, 183–192 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Técher, H., Koundrioukoff, S., Nicolas, A. & Debatisse, M. The impact of replication stress on replication dynamics and DNA damage in vertebrate cells. Nat. Rev. Genet. 18, 535–550 (2017).

    PubMed  Google Scholar 

  5. Scully, R., Panday, A., Elango, R. & Willis, N. A. DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat. Rev. Mol. Cell Biol. 20, 698–714 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Malumbres, M. Cyclin-dependent kinases. Genome Biol. 15, 122 (2014).

    PubMed  PubMed Central  Google Scholar 

  7. Musacchio, A. The molecular biology of spindle assembly checkpoint signaling dynamics. Curr. Biol. 2, R1002–R1018 (2015).

    Google Scholar 

  8. Fisher, R. P. The CDK network: linking cycles of cell division and gene expression. Genes Cancer 3, 731–738 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Simmons Kovacs, L. A., Orlando, D. A. & Haase, S. B. Transcription networks and cyclin/CDKs: the yin and yang of cell cycle oscillators. Cell Cycle 7, 2626–2629 (2008).

    PubMed  Google Scholar 

  10. Morgan, D. O. The Cell Cycle: Principles of Control (New Science Press, 2007).

  11. Bertoli, C., Skotheim, J. M. & De Bruin, R. A. M. Control of cell cycle transcription during G1 and S phases. Nat. Rev. Mol. Cell Biol. 14, 518–528 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Johnson, A. & Skotheim, J. M. Start and the restriction point. Curr. Opin. Cell Biol. 25, 717–723 (2013).

    CAS  PubMed  Google Scholar 

  13. Bertoli, C. & De Bruin, R. A. M. Turning cell cycle entry on its head. eLife 2014, e03475 (2014).

    Google Scholar 

  14. Caillot, M. et al. Cyclin D1 targets hexokinase 2 to control aerobic glycolysis in myeloma cells. Oncogenesis 9, 68 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Sanidas, I. et al. A code of mono-phosphorylation modulates the function of RB. Mol. Cell 73, 985–1000.e6 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Narasimha, A. M. et al. Cyclin D activates the Rb tumor suppressor by mono-phosphorylation. eLife 3, e02872 (2014). Narashima et al. show that cyclin D–CDK4/6 monophosphorylates RB and contrary to the dogma this does not compromise its inhibitory function of E2F-dependent transcription to initiate S phase entry, but it maintains cells in a cell cycle state, preventing their exit.

    PubMed Central  Google Scholar 

  17. Topacio, B. R. et al. Cyclin D-Cdk4,6 drives cell-cycle progression via the retinoblastoma protein’s C-terminal helix. Mol. Cell 74, 758–770.e4 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Zerjatke, T. et al. Quantitative cell cycle analysis based on an endogenous all-in-one reporter for cell tracking and classification. Cell Rep. 19, 1953–1966 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Chung, M. et al. Transient hysteresis in CDK4/6 activity underlies passage of the restriction point in G1. Mol. Cell 76, 562–573.e4 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Yang, H. W. et al. Stress-mediated exit to quiescence restricted by increasing persistence in cdk4/6 activation. eLife 9, e44571 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Cappell, S. D. et al. EMI1 switches from being a substrate to an inhibitor of APC/CCDH1 to start the cell cycle. Nature 558, 313–317 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Barr, A. R., Heldt, F. S., Zhang, T., Bakal, C. & Novák, B. A dynamical framework for the all-or-none G1/S transition. Cell Syst. 2, 27–37 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Crncec, A. & Hochegger, H. Triggering mitosis. FEBS Lett. 593, 2868–2888 (2019).

    CAS  PubMed  Google Scholar 

  24. Hégarat, N. et al. Cyclin a triggers mitosis either via the greatwall kinase pathway or cyclin B. EMBO J. 39, e104419 (2020).

    PubMed  PubMed Central  Google Scholar 

  25. Ha, S. H. & Ferrell, J. E. Thresholds and ultrasensitivity from negative cooperativity. Science 352, 990–993 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Dephoure, N. et al. A quantitative atlas of mitotic phosphorylation. Proc. Natl Acad. Sci. USA 105, 10762–10767 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Blethrow, J. D., Glavy, J. S., Morgan, D. O. & Shokat, K. M. Covalent capture of kinase-specific phosphopeptides reveals Cdk1-cyclin B substrates. Proc. Natl Acad. Sci. USA 105, 1442–1447 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Joukov, V. & De Nicolo, A. Aurora-PLK1 cascades as key signaling modules in the regulation of mitosis. Sci. Signal. 11, eaar4195 (2018).

    PubMed  Google Scholar 

  29. Kettenbach, A. N. et al. Quantitative phosphoproteomics identifies substrates and functional modules of aurora and polo-like kinase activities in mitotic cells. Sci. Signal. 4, rs5 (2011).

    CAS  PubMed  Google Scholar 

  30. Gavet, O. & Pines, J. Progressive activation of cyclinB1-Cdk1 coordinates entry to mitosis. Dev. Cell 18, 533–543 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Taubenberger, A. V., Baum, B. & Matthews, H. K. The mechanics of mitotic cell rounding. Front. Cell Dev. Biol. 8, 687 (2020).

    PubMed  PubMed Central  Google Scholar 

  32. Agircan, F. G., Schiebel, E. & Mardin, B. R. Separate to operate: control of centrosome positioning and separation. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 369, 20130461 (2014).

    PubMed  PubMed Central  Google Scholar 

  33. Gavet, O. & Pines, J. Activation of cyclin B1-Cdk1 synchronizes events in the nucleus and the cytoplasm at mitosis. J. Cell Biol. 189, 247–259 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Santos, S. D. M., Wollman, R., Meyer, T. & Ferrell, J. E. Spatial positive feedback at the onset of mitosis. Cell 149, 1500–1513 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Pines, J. & Hunter, T. Human cyclins A and B1 are differentially located in the cell and undergo cell cycle-dependent nuclear transport. J. Cell Biol. 115, 1–17 (1991).

    CAS  PubMed  Google Scholar 

  36. Hara, M. & Fukagawa, T. Kinetochore assembly and disassembly during mitotic entry and exit. Curr. Opin. Cell Biol. 52, 73–81 (2018).

    CAS  PubMed  Google Scholar 

  37. Foley, E. A. & Kapoor, T. M. Microtubule attachment and spindle assembly checkpoint signalling at the kinetochore. Nat. Rev. Mol. Cell Biol. 14, 25–37 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Geley, S. et al. Anaphase-promoting complex/cyclosome-dependent proteolysis of human cyclin A starts at the beginning of mitosis and is not subject to the spindle assembly checkpoint. J. Cell Biol. 153, 137–147 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Elzen, N. Den & Pines, J. Cyclin A is destroyed in prometaphase and can delay chromosome alignment and anaphase. J. Cell Biol. 153, 121–136 (2001).

    Google Scholar 

  40. Yamano, H. APC/C: current understanding and future perspectives. F1000Res. https://doi.org/10.12688/f1000research.18582.1 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Holder, J., Poser, E. & Barr, F. A. Getting out of mitosis: spatial and temporal control of mitotic exit and cytokinesis by PP1 and PP2A. FEBS Lett. 593, 2908–2924 (2019).

    CAS  PubMed  Google Scholar 

  42. Luo, S. & Tong, L. Structural biology of the separase–securin complex with crucial roles in chromosome segregation. Curr. Opin. Struct. Biol. 49, 114–122 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Vukušić, K., Buđa, R. & Tolić, I. M. Force-generating mechanisms of anaphase in human cells. J. Cell Sci. 132, jcs231985 (2019).

    PubMed  Google Scholar 

  44. Green, A. R., Paluch, E. & Oegema, K. Cytokinesis in animal cells. Annu. Rev. Cell Dev. Biol. 28, 29–58 (2012).

    CAS  PubMed  Google Scholar 

  45. Huang, R.-X. & Zhou, P.-K. DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal. Transduct. Target. Ther. 5, 60 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Matsuoka, S. et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316, 1160–1166 (2007).

    CAS  PubMed  Google Scholar 

  47. Bensimon, A. et al. ATM-dependent and -independent dynamics of the nuclear phosphoproteome after DNA damage. Sci. Signal. 3, rs3 (2010).

    CAS  PubMed  Google Scholar 

  48. Shieh, S. Y., Ahn, J., Tamai, K., Taya, Y. & Prives, C. The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev. 14, 289–300 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Hirao, A. et al. DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science 287, 1824–1827 (2000).

    CAS  PubMed  Google Scholar 

  50. Chehab, N. H., Malikzay, A., Appel, M. & Halazonetis, T. D. Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Genes Dev. 14, 278–288 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Reinhardt, H. C. & Yaffe, M. B. Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2. Curr. Opin. Cell Biol. 21, 245–255 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Brandsma, I. & Gent, D. C. Pathway choice in DNA double strand break repair: observations of a balancing act. Genome Integr. 3, 9 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Janssen, A. & Medema, R. H. Genetic instability: tipping the balance. Oncogene 32, 4459–4470 (2013).

    CAS  PubMed  Google Scholar 

  54. Hafner, A., Bulyk, M. L., Jambhekar, A. & Lahav, G. The multiple mechanisms that regulate p53 activity and cell fate. Nat. Rev. Mol. Cell Biol. 20, 199–210 (2019).

    CAS  PubMed  Google Scholar 

  55. Zeman, M. K. & Cimprich, K. A. Causes and consequences of replication stress. Nat. Cell Biol. 16, 2–9 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Herlihy, A. E. & de Bruin, R. A. M. The role of the transcriptional response to DNA replication stress. Genes 8, 92 (2017).

    PubMed Central  Google Scholar 

  57. Kotsantis, P., Petermann, E. & Boulton, S. J. Mechanisms of oncogene-induced replication stress: jigsaw falling into place. Cancer Discov. 8, 537–555 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Abraham, R. T. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev. 15, 2177–2196 (2001).

    CAS  PubMed  Google Scholar 

  59. Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. McGowan, C. H. & Russell, P. The DNA damage response: sensing and signaling. Curr. Opin. Cell Biol. 16, 629–633 (2004).

    CAS  PubMed  Google Scholar 

  61. Zhang, Y. & Hunter, T. Roles of Chk1 in cell biology and cancer therapy. Int. J. Cancer 134, 1013–1023 (2014).

    CAS  PubMed  Google Scholar 

  62. Rothblum-Oviatt, C. J., Ryan, C. E. & Piwnica-Worms, H. 14-3-3 binding regulates catalytic activity of human Wee1 kinase. Cell Growth Differ. 12, 581–589 (2001).

    CAS  PubMed  Google Scholar 

  63. Lee, J., Kumagai, A. & Dunphy, W. G. Positive regulation of Wee1 by Chk1 and 14-3-3 proteins. Mol. Biol. Cell 12, 551–563 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Lopes, M. et al. The DNA replication checkpoint response stabilizes stalled replication forks. Nature 412, 557–561 (2001).

    CAS  PubMed  Google Scholar 

  65. Feijoo, C. et al. Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing. J. Cell Biol. 154, 913–924 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Tercero, J. A. & Diffley, J. F. X. Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint. Nature 412, 553–557 (2001).

    CAS  PubMed  Google Scholar 

  67. Zachos, G., Rainey, M. D. & Gillespie, D. A. F. Chk1-deficient tumour cells are viable but exhibit multiple checkpoint and survival defects. EMBO J. 22, 713–723 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Petermann, E. et al. Chk1 requirement for high global rates of replication fork progression during normal vertebrate S phase. Mol. Cell. Biol. 26, 3319–3326 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Katsuno, Y. et al. Cyclin A–Cdk1 regulates the origin firing program in mammalian cells. Proc. Natl Acad. Sci. USA 106, 3184–3189 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Petermann, E., Woodcock, M. & Helleday, T. Chk1 promotes replication fork progression by controlling replication initiation. Proc. Natl Acad. Sci. USA 107, 16090–16095 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Conti, C., Seiler, J. A. & Pommier, Y. The mammalian DNA replication elongation checkpoint: implication of Chk1 and relationship with origin firing as determined by single DNA molecule and single cell analyses. Cell Cycle 6, 2760–2767 (2007).

    CAS  PubMed  Google Scholar 

  72. Dimitrova, D. S. & Gilbert, D. M. Temporally coordinated assembly and disassembly of replication factories in the absence of DNA synthesis. Nat. Cell Biol. 2, 686–694 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Yan, S. & Michael, W. M. TopBP1 and DNA polymerase α-mediated recruitment of the 9-1-1 complex to stalled replication forks: implications for a replication restart-based mechanism for ATR checkpoint activation. Cell Cycle 8, 2877–2884 (2009).

    CAS  PubMed  Google Scholar 

  74. El-shemerly, M., Hess, D., Pyakurel, A. K., Moselhy, S. & Ferrari, S. ATR-dependent pathways control hEXO1 stability in response to stalled forks. Nucleic Acids Res. 36, 511–519 (2008).

    CAS  PubMed  Google Scholar 

  75. Casper, A. M., Nghiem, P., Arlt, M. F. & Glover, T. W. ATR regulates fragile site stability. Cell 111, 779–789 (2002).

    CAS  PubMed  Google Scholar 

  76. Trenz, K., Smith, E., Smith, S. & Costanzo, V. ATM and ATR promote Mre11 dependent restart of collapsed replication forks and prevent accumulation of DNA breaks. EMBO J. https://doi.org/10.1038/sj.emboj.7601045 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Hayward, D., Alfonso-Pérez, T. & Gruneberg, U. Orchestration of the spindle assembly checkpoint by CDK1-cyclin B1. FEBS Lett. 593, 2889–2907 (2019).

    CAS  PubMed  Google Scholar 

  78. Grieco, D. & Serpico, A. F. Recent advances in understanding the role of Cdk1 in the spindle assembly checkpoint. F1000Res. https://doi.org/10.12688/f1000research.21185.1 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Yamaguchi, M. et al. Cryo-EM of mitotic checkpoint complex-bound APC/C reveals reciprocal and conformational regulation of ubiquitin ligation. Mol. Cell 63, 593–607 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Alfieri, C. et al. Molecular basis of APC/C regulation by the spindle assembly checkpoint. Nature 536, 431–436 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Sudakin, V., Chan, G. K. T. & Yen, T. J. Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2. J. Cell Biol. 154, 925–936 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Liu, S.-T. & Zhang, H. The mitotic checkpoint complex (MCC): looking back and forth after 15 years. AIMS Mol. Sci. 3, 597–634 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Kapanidou, M., Curtis, N. L. & Bolanos-Garcia, V. M. Cdc20: at the crossroads between chromosome segregation and mitotic exit. Trends Biochem. Sci. 42, 193–205 (2017).

    CAS  PubMed  Google Scholar 

  84. Liu, D., Vader, G., Vromans, M. J. M., Lampson, M. A. & Lens, S. M. A. Sensing chromosome bi-orientation by spatial separation of Aurora B kinase from kinetochore substrates. Science 323, 1350–1353 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Rieder, C. L., Cole, R. W., Khodjakov, A. & Sluder, G. The checkpoint delaying anaphase in response to chromosome monoorientation is mediated by an inhibitory signal produced by unattached kinetochores. J. Cell Biol. 130, 941–948 (1995).

    CAS  PubMed  Google Scholar 

  86. Gascoigne, K. E. & Taylor, S. S. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell 14, 111–122 (2008).

    CAS  PubMed  Google Scholar 

  87. Vitale, I., Manic, G., Castedo, M. & Kroemer, G. Caspase 2 in mitotic catastrophe: the terminator of aneuploid and tetraploid cells. Mol. Cell. Oncol. 4, e1299274 (2017).

    PubMed  PubMed Central  Google Scholar 

  88. Cheng, B. & Crasta, K. Consequences of mitotic slippage for antimicrotubule drug therapy. Endocr. Relat. Cancer 24, T97–T106 (2017).

    CAS  PubMed  Google Scholar 

  89. Brito, D. A. & Rieder, C. L. Mitotic checkpoint slippage in humans occurs via cyclin b destruction in the presence of an active checkpoint. Curr. Biol. 16, 1194–1200 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Fujiwara, T. et al. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437, 1043–1047 (2005).

    CAS  PubMed  Google Scholar 

  91. Thompson, S. L. & Compton, D. A. Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. J. Cell Biol. 188, 369–381 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Sanchez-Vega, F. et al. Oncogenic signaling pathways in the cancer genome atlas. Cell 173, 321–337.e10 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Lecona, E. & Fernandez-Capetillo, O. Targeting ATR in cancer. Nat. Rev. Cancer 18, 586–595 (2018).

    CAS  PubMed  Google Scholar 

  94. Ghelli Luserna Di Rorà, A., Cerchione, C., Martinelli, G. & Simonetti, G. A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target. J. Hematol. Oncol. 13, 1–17 (2020).

    Google Scholar 

  95. Peyressatre, M., Prével, C., Pellerano, M. & Morris, M. C. Targeting cyclin-dependent kinases in human cancers: from small molecules to peptide inhibitors. Cancers 7, 179–237 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Liu, K. et al. The role of CDC25C in cell cycle regulation and clinical cancer therapy: a systematic review. Cancer Cell Int. 20, 1–16 (2020).

    PubMed  PubMed Central  Google Scholar 

  97. Pérez de Castro, I., de Cárcer, G. & Malumbres, M. A census of mitotic cancer genes: new insights into tumor cell biology and cancer therapy. Carcinogenesis 28, 899–912 (2007).

    PubMed  Google Scholar 

  98. Bates, M. et al. Too MAD or not MAD enough: the duplicitous role of the spindle assembly checkpoint protein MAD2 in cancer. Cancer Lett. 469, 11–21 (2020).

    CAS  PubMed  Google Scholar 

  99. Wang, L. et al. Targeting Cdc20 as a novel cancer therapeutic strategy. Pharmacol. Ther. 151, 141–151 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Xie, Y. et al. Mps1/TTK: a novel target and biomarker for cancer. J. Drug Target. 25, 112–118 (2017).

    CAS  PubMed  Google Scholar 

  101. Borah, N. A. & Reddy, M. M. Aurora kinase B inhibition: a potential therapeutic strategy for cancer. Molecules 26, 1981 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  103. Zilfou, J. T. & Lowe, S. W. Tumor suppressive functions of p53. Cold Spring Harb. Perspect. Biol. 1, a001883 (2009).

    PubMed  PubMed Central  Google Scholar 

  104. Chen, J. The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb. Perspect. Med. 6, a026104 (2016).

    PubMed  PubMed Central  Google Scholar 

  105. Chen, H. Z., Tsai, S. Y. & Leone, G. Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat. Rev. Cancer 9, 785–797 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006). Di Micco et al. show that deregulated DNA replication, due to oncogene activation, triggers DNA damage response and cell cycle exit through senescence, establishing the concept of oncogene-induced replication stress driving cancer initiation.

    PubMed  Google Scholar 

  107. Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).

    CAS  PubMed  Google Scholar 

  108. Jones, R. M. et al. Increased replication initiation and conflicts with transcription underlie cyclin E-induced replication stress. Oncogene 32, 3744–3753 (2013).

    CAS  PubMed  Google Scholar 

  109. Bester, A. C. et al. Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell 145, 435–446 (2011). Bester et al. show that replication stress is an early event in cancer development and fuels genome instability, establishing the role of oncogene-induced replication stress in cancer initiation.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Dominguez-Sola, D. et al. Non-transcriptional control of DNA replication by c-Myc. Nature 448, 445–451 (2007).

    CAS  PubMed  Google Scholar 

  111. Swanton, C. et al. Chromosomal instability determines taxane response. Proc. Natl Acad. Sci. USA 106, 8671–8676 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Lee, A. J. X. et al. Chromosomal instability confers intrinsic multidrug resistance. Cancer Res. 71, 1858–1870 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Burrell, R. A. et al. Replication stress links structural and numerical cancer chromosomal instability. Nature 494, 492–496 (2013). Burrell et al. show that replication stress can cause CIN in cancer cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Lecona, E. & Fernández-Capetillo, O. Replication stress and cancer: it takes two to tango. Exp. Cell Res. 329, 26–34 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Wilhelm, T., Said, M. & Naim, V. DNA replication stress and chromosomal instability: dangerous liaisons. Genes (Basel) 11, 642 (2020).

    CAS  Google Scholar 

  117. Bartek, J., Bartkova, J. & Lukas, J. DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene 26, 7773–7779 (2007).

    CAS  PubMed  Google Scholar 

  118. Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005).

    CAS  PubMed  Google Scholar 

  119. Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005).

    CAS  PubMed  Google Scholar 

  120. Taylor, A. M. et al. Genomic and functional approaches to understanding cancer aneuploidy. Cancer Cell 33, 676–689.e3 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Boveri, T. Concerning the origin of malignant tumours by Theodor Boveri. Translated and annotated by Henry Harris. J. Cell Sci. 121, 1–84 (2008).

    PubMed  Google Scholar 

  122. Ganem, N. J. & Pellman, D. Linking abnormal mitosis to the acquisition of DNA damage. J. Cell Biol. 199, 871–881 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Cahill, D. P. et al. Mutations of mitotic checkpoint genes in human cancers. Nature 392, 300–303 (1998).

    CAS  PubMed  Google Scholar 

  124. Ryan, S. D. et al. Up-regulation of the mitotic checkpoint component Mad1 causes chromosomal instability and resistance to microtubule poisons. Proc. Natl Acad. Sci. USA 109, E2205–E2214 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Hernando, E. et al. Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature 430, 797–802 (2004).

    CAS  PubMed  Google Scholar 

  126. Yuan, B. et al. Increased expression of mitotic checkpoint genes in breast cancer cells with chromosomal instability. Clin. Cancer Res. 12, 405–410 (2006).

    CAS  PubMed  Google Scholar 

  127. Sarkar, S. et al. Mitotic checkpoint defects: en route to cancer and drug resistance. Chromosom. Res. 29, 131–144 (2021).

    CAS  Google Scholar 

  128. Sisken, J. E., Bonner, S. V., Grasch, S. D., Powell, D. E. & Donaldson, E. S. Alterations in metaphase durations in cells derived from human tumours. Cell Prolif. 18, 137–146 (1985).

    CAS  Google Scholar 

  129. Therman, E., Buchler, D. A., Nieminen, U. & Timonen, S. Mitotic modifications and aberrations in human cervical cancer. Cancer Genet. Cytogenet. 11, 185–197 (1984).

    CAS  PubMed  Google Scholar 

  130. Kwiatkowski, N. et al. Small-molecule kinase inhibitors provide insight into Mps1 cell cycle function. Nat. Chem. Biol. 6, 359–368 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Stolz, A. et al. Pharmacologic abrogation of the mitotic spindle checkpoint by an indolocarbazole discovered by cellular screening efficiently kills cancer cells. Cancer Res. 69, 3874–3883 (2009).

    CAS  PubMed  Google Scholar 

  132. Siri, S. O., Martino, J. & Gottifredi, V. Structural chromosome instability: types, origins, consequences, and therapeutic opportunities. Cancers (Basel) 13, 3056 (2021).

    Google Scholar 

  133. Janssen, A., van der Burg, M., Szuhai, K., Kops, G. J. P. L. & Medema, R. H. Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science 333, 1895–1898 (2011).

    CAS  PubMed  Google Scholar 

  134. Bakhoum, S. F., Kabeche, L., Murnane, J. P., Zaki, B. I. & Compton, D. A. DNA-damage response during mitosis induces whole-chromosome missegregation. Cancer Discov. 4, 1281–1289 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Funk, L. C., Zasadil, L. M. & Weaver, B. A. Living in CIN: mitotic infidelity and its consequences for tumor promotion and suppression. Dev. Cell 39, 638–652 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Sansregret, L. & Swanton, C. The role of aneuploidy in cancer evolution. Cold Spring Harb. Perspect. Med. 7, 1–18 (2017).

    Google Scholar 

  137. Silk, A. D. et al. Chromosome missegregation rate predicts whether aneuploidy will promote or suppress tumors. Proc. Natl Acad. Sci. USA 110, E4134–E4141 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Zasadil, L. M. et al. High rates of chromosome missegregation suppress tumor progression but do not inhibit tumor initiation. Mol. Biol. Cell 27, 1981–1989 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Birkbak, N. J. et al. Paradoxical relationship between chromosomal instability and survival outcome in cancer. Cancer Res. 71, 3447–3452 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Roylance, R. et al. Relationship of extreme chromosomal instability with long-term survival in a retrospective analysis of primary breast cancer. Cancer Epidemiol. Biomarkers Prev. 20, 2183–2194 (2011).

    PubMed  PubMed Central  Google Scholar 

  141. Sansregret, L. et al. APC/C dysfunction limits excessive cancer chromosomal instability. Cancer Discov. 7, 218–233 (2017). Sansregret et al. show that strengthening the SAC (by APC/C partial depletion) and prolonging mitosis prevents chromosome segregation errors in mitosis and guards against excessive genome instability in cancer cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Pearl, L. H., Schierz, A. C., Ward, S. E., Al-Lazikani, B. & Pearl, F. M. G. Therapeutic opportunities within the DNA damage response. Nat. Rev. Cancer 15, 166–180 (2015).

    CAS  PubMed  Google Scholar 

  143. Mukherjee, S. The Emperor of All Maladies: A Biography of Cancer (Scribner, 2010).

  144. Malumbres, M. & Barbacid, M. Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer 9, 153–166 (2009).

    CAS  PubMed  Google Scholar 

  145. Wagner, V. & Gil, J. Senescence as a therapeutically relevant response to CDK4/6 inhibitors. Oncogene 39, 5165–5176 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Wang, C. et al. Inducing and exploiting vulnerabilities for the treatment of liver cancer. Nature 574, 268–272 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Whittaker, S. R., Mallinger, A., Workman, P. & Clarke, P. A. Inhibitors of cyclin-dependent kinases as cancer therapeutics. Pharmacol. Ther. 173, 83–105 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Sánchez-Martínez, C., Lallena, M. J., Sanfeliciano, S. G. & de Dios, A. Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: recent advances (2015–2019). Bioorg. Med.Chem. Lett. 29, 126637 (2019).

    PubMed  Google Scholar 

  149. Choi, Y. J. & Anders, L. Signaling through cyclin D-dependent kinases. Oncogene 33, 1890–1903 (2014).

    CAS  PubMed  Google Scholar 

  150. Álvarez-Fernández, M. & Malumbres, M. Mechanisms of sensitivity and resistance to CDK4/6 inhibition. Cancer Cell 37, 514–529 (2020).

    PubMed  Google Scholar 

  151. Spring, L. M. et al. Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. Lancet 395, 817–827 (2020).

    CAS  PubMed  Google Scholar 

  152. Guiley, K. Z. et al. p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition. Science 366, eaaw2106 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Persky, N. S. et al. Defining the landscape of ATP-competitive inhibitor resistance residues in protein kinases. Nat. Struct. Mol. Biol. 27, 92–104 (2020).

    CAS  PubMed  Google Scholar 

  154. Schade, A. E., Oser, M. G., Nicholson, H. E. & DeCaprio, J. A. Cyclin D-CDK4 relieves cooperative repression of proliferation and cell cycle gene expression by DREAM and RB. Oncogene 38, 4962–4976 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Ruscetti, M. et al. NK cell–mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science 362, 1416–1422 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Ruscetti, M. et al. Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer. Cell 181, 424–441.e21 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Christensen, C. L. et al. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell 26, 909–922 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Patel, H. et al. ICEC0942, an orally bioavailable selective inhibitor of CDK7 for cancer treatment. Mol. Cancer Ther. 17, 1156 LP–1151166 (2018).

    Google Scholar 

  159. Greenall, S. A. et al. Cyclin-dependent kinase 7 is a therapeutic target in high-grade glioma. Oncogenesis 6, e336 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Eliades, P. et al. High MITF expression is associated with super-enhancers and suppressed by CDK7 inhibition in melanoma. J. Invest. Dermatol. 138, 1582–1590 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Zhong, L., Yang, S., Jia, Y. & Lei, K. Inhibition of cyclin-dependent kinase 7 suppresses human hepatocellular carcinoma by inducing apoptosis. J. Cell. Biochem. 119, 9742–9751 (2018).

    CAS  PubMed  Google Scholar 

  162. Cao, X. et al. Targeting super-enhancer-driven oncogenic transcription by CDK7 inhibition in anaplastic thyroid carcinoma. Thyroid 29, 809–823 (2019).

    CAS  PubMed  Google Scholar 

  163. Lu, P. et al. THZ1 reveals CDK7-dependent transcriptional addictions in pancreatic cancer. Oncogene 38, 3932–3945 (2019).

    CAS  PubMed  Google Scholar 

  164. Zhong, S., Zhang, Y., Yin, X. & Di, W. CDK7 inhibitor suppresses tumor progression through blocking the cell cycle at the G2/M phase and inhibiting transcriptional activity in cervical cancer. Onco. Targets. Ther. 12, 2137–2147 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Zhang, Y. et al. The covalent CDK7 inhibitor THZ1 potently induces apoptosis in multiple myeloma cells in vitro and in vivo. Clin. Cancer Res. 25, 6195–6205 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Schachter, M. M. & Fisher, R. P. The CDK-activating kinase Cdk7. Cell Cycle 12, 3239–3240 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Sava, G. P., Fan, H., Coombes, R. C., Buluwela, L. & Ali, S. CDK7 inhibitors as anticancer drugs. Cancer Metastasis Rev. 39, 805–823 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Barr, A. R. et al. DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression. Nat. Commun. 8, 14728 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Shiohara, M., Koike, K., Komiyama, A. & Koeffler, H. P. p21WAF1 mutations and human malignancies. Leuk. Lymphoma 26, 35–41 (1997).

    CAS  PubMed  Google Scholar 

  170. Hirai, H. et al. Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol. Cancer Ther. 8, 2992–3000 (2009).

    CAS  PubMed  Google Scholar 

  171. Matheson, C. J., Backos, D. S. & Reigan, P. Targeting WEE1 kinase in cancer. Trends Pharmacol. Sci. 37, 872–881 (2016).

    CAS  PubMed  Google Scholar 

  172. Moens, S. et al. The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers. Sci. Rep. 11, 3176 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Shamloo, B. & Usluer, S. p21 in cancer research. Cancers (Basel) 11, 1178 (2019).

    CAS  Google Scholar 

  174. Macheret, M. & Halazonetis, T. D. DNA replication stress as a hallmark of cancer. Annu. Rev. Pathol. 10, 425–448 (2015).

    CAS  PubMed  Google Scholar 

  175. Murga, M. et al. Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nat. Struct. Mol. Biol. 18, 1331–1335 (2011). Murga et al. show that inhibition of ATR and CHK1 can kill cells with oncogene-induced replication stress, establishing that targeting the replication stress response can selectively kill cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Toledo, L. I., Murga, M. & Fernandez-Capetillo, O. Targeting ATR and Chk1 kinases for cancer treatment: a new model for new (and old) drugs. Mol. Oncol. 5, 368–373 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Toledo, L. I. et al. A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat. Struct. Mol. Biol. 18, 721–727 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. León, T. E. et al. EZH2-deficient T-cell acute lymphoblastic leukemia is sensitized to CHK1 Inhibition through enhanced replication stress. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-19-0789 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Rogers, R. F. et al. CHK1 inhibition is synthetically lethal with loss of B-family DNA polymerase function in human lung and colorectal cancer cells. Cancer Res. 80, 1735–1747 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Qiu, Z., Oleinick, N. L. & Zhang, J. ATR/CHK1 inhibitors and cancer therapy. Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol. 126, 450–464 (2018).

    CAS  Google Scholar 

  181. Forment, J. V. & O’Connor, M. J. Targeting the replication stress response in cancer. Pharmacol. Ther. 188, 155–167 (2018).

    CAS  PubMed  Google Scholar 

  182. Eykelenboom, J. K. et al. ATR Activates the S-M checkpoint during unperturbed growth to ensure sufficient replication prior to mitotic onset. Cell Rep. 5, 1095–1107 (2013).

    CAS  PubMed  Google Scholar 

  183. Bertoli, C., Herlihy, A. E., Pennycook, B. R., Kriston-Vizi, J. & De Bruin, R. A. M. Sustained E2F-dependent transcription is a key mechanism to prevent replication-stress-induced DNA damage. Cell Rep. 15, 1412–1422 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Penna, L. S., Henriques, J. A. P. & Bonatto, D. Anti-mitotic agents: are they emerging molecules for cancer treatment? Pharmacol. Ther. 173, 67–82 (2017).

    CAS  PubMed  Google Scholar 

  185. Weaver, B. A. How taxol/paclitaxel kills cancer cells. Mol. Biol. Cell 25, 2677–2681 (2014).

    PubMed  PubMed Central  Google Scholar 

  186. Zasadil, L. M. et al. Cytotoxicity of paclitaxel in breast cancer is due to chromosome missegregation on multipolar spindles. Sci. Transl. Med. 6, 1–10 (2014). Zasadil et al. show that the cytotoxic effects of paclitaxel at clinically relevant concentrations (as measured in human tumours) are not due to prolonged SAC activation and mitotic arrest but rather are due to chromosome segregation defects that result in unviable karyotypes and cell death.

    Google Scholar 

  187. Tischer, J. & Gergely, F. Anti-mitotic therapies in cancer. J. Cell Biol. 218, 10–11 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Yan, V. C. et al. Why great mitotic inhibitors make poor cancer drugs. Trends Cancer 6, 924–941 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Myers, S. M. & Collins, I. Recent findings and future directions for interpolar mitotic kinesin inhibitors in cancer therapy. Future Med. Chem. 8, 463–489 (2016).

    CAS  PubMed  Google Scholar 

  190. Borisa, A. C. & Bhatt, H. G. A comprehensive review on Aurora kinase: small molecule inhibitors and clinical trial studies. Eur. J. Med. Chem. 140, 1–19 (2017).

    CAS  PubMed  Google Scholar 

  191. Gutteridge, R. E. A., Ndiaye, M. A., Liu, X. & Ahmad, N. Plk1 inhibitors in cancer therapy: from laboratory to clinics. Mol. Cancer Ther. 15, 1427–1435 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. El-Arabey, A. A., Salama, S. A. & Abd-Allah, A. R. CENP-E as a target for cancer therapy: where are we now? Life Sci. 208, 192–200 (2018).

    CAS  PubMed  Google Scholar 

  193. Rowald, K. et al. Negative selection and chromosome instability induced by Mad2 overexpression delay breast cancer but facilitate oncogene-independent outgrowth. Cell Rep. 15, 2679–2691 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Maia, A. R. R. et al. Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell division. Br. J. Cancer 118, 1586–1595 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Cohen-Sharir, Y. et al. Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition. Nature 590, 486–491 (2021). Cohen-Sharir et al. show that aneuploid cells are more sensitive to SAC inhibition than diploid cells. Aneuploid cells were found to depend on an intact SAC for accurate chromosome segregation and long-term survival, implicating the SAC as a potential therapeutic target in aneuploid cancers.

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Simon Serrano, S. et al. Inhibition of mitotic kinase Mps1 promotes cell death in neuroblastoma. Sci. Rep. 10, 11997 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Wengner, A. M. et al. Novel Mps1 kinase inhibitors with potent antitumor activity. Mol. Cancer Ther. 15, 583–592 (2016).

    CAS  PubMed  Google Scholar 

  198. Alimova, I. et al. MPS1 kinase as a potential therapeutic target in medulloblastoma. Oncol. Rep. 36, 2633–2640 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Siemeister, G. et al. Inhibition of BUB1 kinase by Bay 1816032 sensitizes tumor cells toward taxanes, ATR, and PARP inhibitors in vitro and in vivo. Clin. Cancer Res. 25, 1404–1414 (2019).

    CAS  PubMed  Google Scholar 

  200. Silva, P. M. A. et al. Suppression of spindly delays mitotic exit and exacerbates cell death response of cancer cells treated with low doses of paclitaxel. Cancer Lett. 394, 33–42 (2017).

    CAS  PubMed  Google Scholar 

  201. Finn, R. S., Aleshin, A. & Slamon, D. J. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res. 18, 17 (2016).

    PubMed  PubMed Central  Google Scholar 

  202. Fry, D. W. et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol. Cancer Ther. 3, 1427–1438 (2004).

    CAS  PubMed  Google Scholar 

  203. Hortobagyi, G. N. et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N. Engl. J. Med. 375, 1738–1748 (2016).

    CAS  PubMed  Google Scholar 

  204. Rader, J. et al. Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin. Cancer Res. 19, 6173–6182 (2013).

    CAS  PubMed  Google Scholar 

  205. Tripathy, D. et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 19, 904–915 (2018).

    CAS  PubMed  Google Scholar 

  206. Sledge, G. W. Jr. Curing metastatic breast cancer. J. Oncol. Pract. 12, 6–10 (2016).

    PubMed  Google Scholar 

  207. Dickler, M. N. et al. MONARCH 1, A phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2− metastatic breast cancer. Clin. Cancer Res. 23, 5218–5224 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Gelbert, L. M. et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest. N. Drugs 32, 825–837 (2014).

    CAS  Google Scholar 

  209. Schulze, V. K. et al. Treating cancer by spindle assembly checkpoint abrogation: discovery of two clinical candidates, BAY 1161909 and BAY 1217389, targeting MPS1 kinase. J. Med. Chem. 63, 8025–8042 (2020).

    CAS  PubMed  Google Scholar 

  210. DePamphilis, M. L. Genome duplication at the beginning of mammalian development. Curr. Top. Dev. Biol. 120, 55–102 (2016).

    CAS  PubMed  Google Scholar 

  211. Arias, E. E. & Walter, J. C. Strength in numbers: preventing rereplication via multiple mechanisms in eukaryotic cells. Genes Dev. 21, 497–518 (2007).

    CAS  PubMed  Google Scholar 

  212. Davidson, I. F., Li, A. & Blow, J. J. Deregulated replication licensing causes DNA fragmentation consistent with head-to-tail fork collision. Mol. Cell 24, 433–443 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Neelsen, K. J. et al. Deregulated origin licensing leads to chromosomal breaks by rereplication of a gapped DNA template. Genes Dev. 27, 2537–2542 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Fragkos, M., Ganier, O., Coulombe, P. & Méchali, M. DNA replication origin activation in space and time. Nat. Rev. Mol. Cell Biol. 16, 360–374 (2015).

    CAS  PubMed  Google Scholar 

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Acknowledgements

R.A.M.d.B. and C.B. are supported by core funding from the MRC–UCL University Unit (reference MC_EX_G0800785) and R.A.M.d.B.’s Cancer Research UK Programme Foundation Award. H.K.M received funding from a CRUK–EPSRC Multidisciplinary Project Award (C1529/A23335). The authors thank J. Pines and J. Downs for helpful discussions and A. Barr and the peer reviewers for critical reading of the manuscript. They apologize to colleagues whose work could be cited only indirectly.

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  1. MRC Laboratory for Molecular Cell Biology, University College London, London, UK

    Helen K. Matthews, Cosetta Bertoli & Robertus A. M. de Bruin

  2. Department of Biomedical Science, University of Sheffield, Sheffield, UK

    Helen K. Matthews

  3. UCL Cancer Institute, University College London, London, UK

    Robertus A. M. de Bruin

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Glossary

Cyclin-dependent kinases

(CDKs). CDKs depend on cyclins for their kinase activity. The levels of cyclins increase during the cell cycle and cyclin–CDK complex activity drives cell cycle progression by phosphorylating protein targets.

Quiescence

A reversible cellular state, outside G1 phase, from which cells can re-enter the cell cycle.

Anaphase-promoting complex/cyclosome

(APC/C). Ubiquitin ligase complex activity that is restricted to mitosis and G1 phase and is required to initiate exit from mitosis and indirectly for DNA replication.

DNA end resection

Removal of nucleotides by exonucleases involved in repairing DNA, exposing tracks of single-stranded DNA at sites of double-strand break repair. It is required for homologous recombination.

Non-homologous end joining

DNA double-strand break repair mechanism based on the juxtaposition of two pieces of DNA.

Homologous recombination

Mechanism of DNA double-strand break repair requiring the presence of duplicated chromatids, occurring only in S and G2 phases. It requires the resection of DNA ends at the break site.

Senescence

A non-reversible cellular state, outside G1 phase, from which cells cannot re-enter the cell cycle.

Genome instability

Stochastic acquisition of genetic change over many cell divisions that can result in mutations and chromosomal rearrangements and aneuploidy.

Chromosomal instability

(CIN). Type of genome instability involving structural and/or numerical chromosome aberrations.

Aneuploidy

Abnormal number of chromosomes in a cell.

Senolytics

Compounds that selectively kill cells that are in a state of senescence.

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Matthews, H.K., Bertoli, C. & de Bruin, R.A.M. Cell cycle control in cancer. Nat Rev Mol Cell Biol 23, 74–88 (2022). https://doi.org/10.1038/s41580-021-00404-3

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