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Annual Review of Cancer Biology

Volume 1, 2017

Cell Cycle–Targeted Cancer Therapies

Abstract

A cardinal feature of cancer cells is the deregulation of cell cycle controls. Targeted drug therapy is designed to take advantage of specific genetic alterations that distinguish tumor cells from their normal counterparts. Mutated oncogenes and inactivated tumor suppressors can increase the dependency of cancer cells on G-phase cyclin-dependent kinases, augment replication stress and DNA damage during S phase, and dismantle checkpoints that monitor progression through S/G/M. These acquired defects generate cancer cell–specific vulnerabilities that provide a window of opportunity for targeted cancer treatments. We review the basic principles underlying the design of targeted therapies with emphasis on two main features: oncogene addiction and synthetic lethality. We discuss how traditional cytotoxic agents may depend, with relatively less specificity, on these same features and then point to examples of the successful application of newly developed, targeted therapeutic agents that offer reduced, dose-limiting toxicities to normal cells.

Keyword(s): cancer treatment, CDKs, cell cycle checkpoints, cyclin-dependent kinases, genotoxic damage, oncogene addiction, synthetic lethality
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/content/journals/10.1146/annurev-cancerbio-040716-075628
2017-03-06
2024-04-25
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Literature Cited

  1. Aarts M, Linardopoulos S, Turner NC. 2013. Tumour selective targeting of cell cycle kinases for cancer treatment. Curr. Opin. Pharmacol. 13:529–35 [Google Scholar]
  2. Aarts M, Sharpe R, Garcia-Murillas I, Gevensleben H, Hurd MS. et al. 2012. Forced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1. Cancer Discov 2:524–39 [Google Scholar]
  3. Ahn J, Urist M, Prives C. 2004. The Chk2 protein kinase. DNA Repair 3:1039–47 [Google Scholar]
  4. Al-Lazikani B, Banerji U, Workman P. 2012. Combinatorial drug therapy for cancer in the post-genomic era. Nat. Biotechnol. 30:679–92 [Google Scholar]
  5. Alt JR, Cleveland JL, Hannink M, Diehl JA. 2000. Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev 14:3102–14 [Google Scholar]
  6. Anders L, Ke N, Hydbring P, Choi YJ, Widlund HR. et al. 2011. A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell 20:620–34Identifies FOXM1 as an atypical, non-RB-family CDK4 and CDK6 substrate. [Google Scholar]
  7. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. 2015. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov. 14:130–46 [Google Scholar]
  8. Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G. 1993. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev 7:812–21 [Google Scholar]
  9. Banin S, Moyal L, Shieh S, Taya Y, Anderson CW. et al. 1998. Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281:1674–77 [Google Scholar]
  10. Bartek J, Bartkova J, Lukas J. 1996. The retinoblastoma protein pathway and the restriction point. Curr. Opin. Cell Biol. 8:805–14 [Google Scholar]
  11. Bartek J, Bartkova J, Lukas J. 2007. DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene 26:7773–79 [Google Scholar]
  12. Bartek J, Lukas J. 2003. Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3:421–29 [Google Scholar]
  13. Bartek J, Lukas J. 2007. DNA damage checkpoints: from initiation to recovery or adaptation. Curr. Opin. Cell Biol. 19:238–45 [Google Scholar]
  14. Bartek J, Mistrik M, Bartkova J. 2012. Thresholds of replication stress signaling in cancer development and treatment. Nat. Struct. Mol. Biol. 19:5–7 [Google Scholar]
  15. Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F. et al. 2005. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434:864–70 [Google Scholar]
  16. Bauer NC, Corbett AH, Doetsch PW. 2015. The current state of eukaryotic DNA base damage and repair. Nucleic Acids Res 43:10083–101 [Google Scholar]
  17. Bayliss R, Fry A, Haq T, Yeoh S. 2012. On the molecular mechanisms of mitotic kinase activation. Open Biol 2:120136 [Google Scholar]
  18. Beck H, Nahse-Kumpf V, Larsen MS, O'Hanlon KA, Patzke S. et al. 2012. Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption. Mol. Cell. Biol. 32:4226–36 [Google Scholar]
  19. Bouwman P, Aly A, Escandell JM, Pieterse M, Bartkova J. et al. 2010. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat. Struct. Mol. Biol. 17:688–95 [Google Scholar]
  20. Branzei D, Foiani M. 2010. Maintaining genome stability at the replication fork. Nat. Rev. Mol. Cell. Biol. 11:208–19 [Google Scholar]
  21. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D. et al. 2005. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–17Demonstrates that PARP inhibition causes synthetic lethality in BRCA2-deficient tumors (also see Farmer et al. 2005). [Google Scholar]
  22. Bunting SF, Callen E, Wong N, Chen HT, Polato F. et al. 2010. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141:243–54 [Google Scholar]
  23. Burkhart DL, Sage J. 2008. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat. Rev. Cancer 8:671–82 [Google Scholar]
  24. Burrell RA, McClelland SE, Endesfelder D, Groth P, Weller MC. et al. 2013a. Replication stress links structural and numerical cancer chromosomal instability. Nature 494:492–96 [Google Scholar]
  25. Burrell RA, McGranahan N, Bartek J, Swanton C. 2013b. The causes and consequences of genetic heterogeneity in cancer evolution. Nature 501:338–45 [Google Scholar]
  26. Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K. et al. 1998. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281:1677–79 [Google Scholar]
  27. Carrano AC, Eytan E, Hershko A, Pagano M. 1999. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat. Cell Biol. 1:193–99 [Google Scholar]
  28. Chen HZ, Tsai SY, Leone G. 2009. Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat. Rev. Cancer 9:785–97 [Google Scholar]
  29. Choi YJ, Anders L. 2014. Signaling through cyclin D-dependent kinases. Oncogene 33:1890–903 [Google Scholar]
  30. Christensen CL, Kwiatkowski N, Abraham BJ, Carretero J, Al-Shahrour F. et al. 2014. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell 26:909–22 [Google Scholar]
  31. Ciccia A, Elledge SJ. 2010. The DNA damage response: making it safe to play with knives. Mol. Cell 40:179–204 [Google Scholar]
  32. Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P. et al. 2006. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444:638–42 [Google Scholar]
  33. Diaz-Moralli S, Tarrado-Castellarnau M, Miranda A, Cascante M. 2013. Targeting cell cycle regulation in cancer therapy. Pharmacol. Ther. 138:255–71 [Google Scholar]
  34. Diehl JA, Cheng M, Roussel MF, Sherr CJ. 1998. Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 12:3499–511 [Google Scholar]
  35. Dietlein F, Kalb B, Jokic M, Noll EM, Strong A. et al. 2015. A synergistic interaction between Chk1- and MK2 inhibitors in KRAS-mutant cancer. Cell 162:146–59Demonstrates that two checkpoint inhibitors trigger mitotic catastrophe and apoptosis in mutant KRAS- and BRAF-driven tumor cells. [Google Scholar]
  36. Diffley JF. 2004. Regulation of early events in chromosome replication. Curr. Biol. 14:R778–86 [Google Scholar]
  37. Domingo-Sananes MR, Kapuy O, Hunt T, Novak B. 2011. Switches and latches: a biochemical tug-of-war between the kinases and phosphatases that control mitosis. Philos. Trans. R. Soc. Lond. B 366:3584–94 [Google Scholar]
  38. Dominguez-Brauer C, Thu KL, Mason JM, Blaser H, Bray MR. et al. 2015. Targeting mitosis in cancer: emerging strategies. Mol. Cell 60:524–36 [Google Scholar]
  39. Dyson N. 1998. The regulation of E2F by pRB-family proteins. Genes Dev 12:2245–62 [Google Scholar]
  40. El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R. et al. 1993. Waf1, a potential mediator of p53 tumor suppression. Cell 75:817–25 [Google Scholar]
  41. Ewen ME, Sluss HK, Sherr CJ, Matsushime H, Kato J. et al. 1993. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Cell 73:487–97 [Google Scholar]
  42. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA. et al. 2005. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–21Reveals that PARP inhibition causes synthetic lethality in BRCA2-deficient tumors (also see Bryant et al. 2005). [Google Scholar]
  43. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM. et al. 2015. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 16:25–35Provides a report of the Phase II trial that led to US FDA approval of palbociclib treatment for estrogen receptor–positive breast cancer. [Google Scholar]
  44. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M. et al. 2004. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol. Cancer Ther. 3:1427–38 [Google Scholar]
  45. Fung TK, Ma HT, Poon RY. 2007. Specialized roles of the two mitotic cyclins in somatic cells: cyclin A as an activator of M phase-promoting factor. Mol. Biol. Cell 18:1861–73 [Google Scholar]
  46. Fung TK, Poon RY. 2005. A roller coaster ride with the mitotic cyclins. Semin. Cell Dev. Biol. 16:335–42 [Google Scholar]
  47. Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA. et al. 2016. Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell 29:255–69 [Google Scholar]
  48. Goldstein M, Kastan MB. 2015. The DNA damage response: implications for tumor responses to radiation and chemotherapy. Annu. Rev. Med. 66:129–43 [Google Scholar]
  49. Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A. et al. 2005. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434:907–13 [Google Scholar]
  50. Guo R, Zheng L, Park JW, Lv R, Chen H. et al. 2014. BS69/ZMYND11 reads and connects histone H3.3 lysine 36 trimethylation-decorated chromatin to regulated pre-mRNA processing. Mol. Cell 56:298–310 [Google Scholar]
  51. Halazonetis TD, Gorgoulis VG, Bartek J. 2008. An oncogene-induced DNA damage model for cancer development. Science 319:1352–55 [Google Scholar]
  52. Hall M, Peters G. 1996. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv. Cancer Res. 68:67–108 [Google Scholar]
  53. Hartwell LH, Weinert TA. 1989. Checkpoints—controls that ensure the order of cell cycle events. Science 246:629–34 [Google Scholar]
  54. Hills SA, Diffley JF. 2014. DNA replication and oncogene-induced replicative stress. Curr. Biol. 24:R435–44 [Google Scholar]
  55. Hirai H, Iwasawa Y, Okada M, Arai T, Nishibata T. et al. 2009. 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 [Google Scholar]
  56. Hitomi M, Stacey DW. 2001. Ras-dependent cell cycle commitment during G2 phase. FEBS Lett 490:123–31 [Google Scholar]
  57. Hoeijmakers JH. 2001. Genome maintenance mechanisms for preventing cancer. Nature 411:366–74 [Google Scholar]
  58. Hsu JY, Reimann JD, Sorensen CS, Lukas J, Jackson PK. 2002. E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APCCdh1. Nat. Cell Biol. 4:358–66 [Google Scholar]
  59. Huang CH, Lujambio A, Zuber J, Tschaharganeh DF, Doran MG. et al. 2014. CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. Genes Dev 28:1800–14 [Google Scholar]
  60. Huang HC, Shi J, Orth JD, Mitchison TJ. 2009. Evidence that mitotic exit is a better cancer therapeutic target than spindle assembly. Cancer Cell 16:347–58Establishes that by blocking mitotic exit by targeting the APC subunit, CDC20 bypasses mitotic slippage and triggers apoptosis. [Google Scholar]
  61. Hunt T. 1991. Cyclins and their partners: from a simple idea to reality. Semin. Cell Biol. 2:213–22 [Google Scholar]
  62. Jackson JR, Patrick DR, Dar MM, Huang PS. 2007. Targeted anti-mitotic therapies: Can we improve on tubulin agents. Nat. Rev. Cancer 7:107–17 [Google Scholar]
  63. Jackson SP, Bartek J. 2009. The DNA-damage response in human biology and disease. Nature 461:1071–78 [Google Scholar]
  64. 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]
  65. Jasin M, Rothstein R. 2013. Repair of strand breaks by homologous recombination. Cold Spring Harb. Perspect. Biol. 5:a012740 [Google Scholar]
  66. Kaelin WG Jr. 2005. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 5:689–98 [Google Scholar]
  67. Kastan MB, Bartek J. 2004. Cell-cycle checkpoints and cancer. Nature 432:316–23 [Google Scholar]
  68. Kato J, Matsushime H, Hiebert SW, Ewen ME, Sherr CJ. 1993. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev 7:331–42 [Google Scholar]
  69. Keen N, Taylor S. 2004. Aurora-kinase inhibitors as anticancer agents. Nat. Rev. Cancer 4:927–36 [Google Scholar]
  70. Kim WY, Sharpless NE. 2006. The regulation of INK4/ARF in cancer and aging. Cell 127:265–75 [Google Scholar]
  71. Koh J, Enders GH, Dynlacht BD, Harlow E. 1995. Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition. Nature 375:506–10 [Google Scholar]
  72. 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]
  73. Kruiswijk F, Labuschagne CF, Vousden KH. 2015. p53 in survival, death, and metabolic health: a lifeguard with a licence to kill. Nat. Rev. Mol. Cell. Biol 16:393–405 [Google Scholar]
  74. Kunkel TA. 2015. Celebrating DNA's repair crew. Cell 163:1301–3 [Google Scholar]
  75. Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J. et al. 2014. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511:616–20Reports the discovery and characterization of a covalent CDK7 inhibitor that targets the core transcriptional circuitry. [Google Scholar]
  76. Lanni JS, Jacks T. 1998. Characterization of the p53-dependent postmitotic checkpoint following spindle disruption. Mol. Cell Biol. 18:1055–64 [Google Scholar]
  77. Levine AJ, Oren M. 2009. The first 30 years of p53: growing ever more complex. Nat. Rev. Cancer 9:749–58 [Google Scholar]
  78. Lindqvist A, Rodriguez-Bravo V, Medema RH. 2009. The decision to enter mitosis: feedback and redundancy in the mitotic entry network. J. Cell Biol. 185:193–202 [Google Scholar]
  79. Lord CJ, Ashworth A. 2012. The DNA damage response and cancer therapy. Nature 481:287–94 [Google Scholar]
  80. Lord CJ, Ashworth A. 2013. Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nat. Med. 19:1381–88 [Google Scholar]
  81. Lord CJ, Ashworth A. 2016. BRCAness revisited. Nat. Rev. Cancer 16:110–20 [Google Scholar]
  82. Lord CJ, Tutt AN, Ashworth A. 2015. Synthetic lethality and cancer therapy: lessons learned from the development of PARP inhibitors. Annu. Rev. Med. 66:455–70 [Google Scholar]
  83. Lu H, Xue Y, Yu GK, Arias C, Lin J. et al. 2015. Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism. eLife 4:e06535Demonstrates that combined inhibition of CDK9 and BRD4 causes genome-wide polymerase II pausing and triggers cell death. [Google Scholar]
  84. Ludlow JW, Shon J, Pipas JM, Livingston DM, DeCaprio JA. 1990. The retinoblastoma susceptibility gene product undergoes cell cycle-dependent dephosphorylation and binding to and release from SV40 large T. Cell 60:387–96 [Google Scholar]
  85. Lukas J, Parry D, Aagaard L, Mann DJ, Bartkova J. et al. 1995. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature 375:503–6 [Google Scholar]
  86. Luo J, Solomini NL, Elledge SJ. 2009. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136:823–37 [Google Scholar]
  87. Malkova A, Haber JE. 2012. Mutations arising during repair of chromosome breaks. Annu. Rev. Genet. 46:455–73 [Google Scholar]
  88. Malumbres M. 2014. Cyclin-dependent kinases. Genome Biol 15:122 [Google Scholar]
  89. Malumbres M, Sotillo R, Santamaria D, Galan J, Cerezo A. et al. 2004. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118:493–504 [Google Scholar]
  90. Manning AL, Dyson NJ. 2012. RB: mitotic implications of a tumour suppressor. Nat. Rev. Cancer 12:220–26 [Google Scholar]
  91. Marcus AI, Peters U, Thomas SL, Garrett S, Zelnak A. et al. 2005. Mitotic kinesin inhibitors induce mitotic arrest and cell death in Taxol-resistant and -sensitive cancer cells. J. Biol. Chem. 280:11569–77 [Google Scholar]
  92. Matsushime H, Ewen ME, Strom DK, Kato JY, Hanks SK. et al. 1992. Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell 71:323–34 [Google Scholar]
  93. McGarry TJ, Kirschner MW. 1998. Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell 93:1043–53 [Google Scholar]
  94. Medema RH, Herrera RE, Lam F, Weinberg RA. 1995. Growth suppression by p16ink4 requires functional retinoblastoma protein. PNAS 92:6289–93 [Google Scholar]
  95. Meyerson M, Harlow E. 1994. Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol. Cell. Biol. 14:2077–86 [Google Scholar]
  96. Miller JJ, Summers MK, Hansen DV, Nachury MV, Lehman NL. et al. 2006. Emi1 stably binds and inhibits the anaphase-promoting complex/cyclosome as a pseudosubstrate inhibitor. Genes Dev 20:2410–20 [Google Scholar]
  97. Moding EJ, Kastan MB, Kirsch DG. 2013. Strategies for optimizing the response of cancer and normal tissues to radiation. Nat. Rev. Drug Discov. 12:526–42 [Google Scholar]
  98. Moynahan ME, Jasin M. 2010. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat. Rev. Mol. Cell. Biol. 11:196–207 [Google Scholar]
  99. Murga M, Campaner S, Lopez-Contreras AJ, Toledo LI, Soria R. et al. 2011. Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nat. Struct. Mol. Biol. 18:1331–35 [Google Scholar]
  100. Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL. 2011. Cyclin D as a therapeutic target in cancer. Nat. Rev. Cancer 11:558–72 [Google Scholar]
  101. Nakayama KI, Nakayama K. 2006. Ubiquitin ligases: cell-cycle control and cancer. Nat. Rev. Cancer 6:369–81 [Google Scholar]
  102. Nevins JR. 1998. Toward an understanding of the functional complexity of the E2F and retinoblastoma families. Cell Growth Differ 9:585–93 [Google Scholar]
  103. Nicolay BN, Danielian PS, Kottakis F, Lapek JD Jr, Sanidas I. et al. 2015. Proteomic analysis of pRb loss highlights a signature of decreased mitochondrial oxidative phosphorylation. Genes Dev 29:1875–89 [Google Scholar]
  104. Nigg EA. 2001. Mitotic kinases as regulators of cell division and its checkpoints. Nat. Rev. Mol. Cell Biol. 2:21–32 [Google Scholar]
  105. Norbury C, Nurse P. 1992. Animal cell cycles and their control. Annu. Rev. Biochem. 61:441–70 [Google Scholar]
  106. O'Connor MJ. 2015. Targeting the DNA damage response in cancer. Mol. Cell 60:547–60 [Google Scholar]
  107. Ortega S, Malumbres M, Barbacid M. 2002. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim. Biophys. Acta 1602:73–87 [Google Scholar]
  108. Orth JD, Tang Y, Shi J, Loy CT, Amendt C. et al. 2008. Quantitative live imaging of cancer and normal cells treated with kinesin-5 inhibitors indicates significant differences in phenotypic responses and cell fate. Mol. Cancer Ther. 7:3480–89 [Google Scholar]
  109. Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G. et al. 1995. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 269:682–85 [Google Scholar]
  110. Pagliarini R, Shao W, Sellers WR. 2015. Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure. EMBO Rep 16:280–96 [Google Scholar]
  111. Pelish HE, Liau BB, Nitulescu II, Tangpeerachaikul A Poss ZC. et al. 2015. Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature 526:273–76 [Google Scholar]
  112. Perry JA, Kornbluth S. 2007. Cdc25 and Wee1: analogous opposites. Cell Div 2:12 [Google Scholar]
  113. Pfister SX, Markkanen E, Jiang Y, Sarkar S, Woodcock M. et al. 2015. Inhibiting WEE1 selectively kills histone H3K36me3-deficient cancers by dNTP starvation. Cancer Cell 28:557–68Demonstrates that WEE1 inhibition induces synthetic lethality in cancers deficient in H3K36me3 and ribonucleotide reductase expression. [Google Scholar]
  114. Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J. et al. 1994. P27Kip1, a cyclin–Cdk inhibitor, links transforming growth factor-β and contact inhibition to cell cycle arrest. Genes Dev 8:9–22 [Google Scholar]
  115. Reardon JT, Sancar A. 2005. Nucleotide excision repair. Prog. Nucleic Acid Res. Mol. Biol. 79:183–235 [Google Scholar]
  116. Reinhardt HC, Yaffe MB. 2013. Phospho-Ser/Thr-binding domains: navigating the cell cycle and DNA damage response. Nat. Rev. Mol. Cell Biol. 14:563–80 [Google Scholar]
  117. Reyes GX, Schmidt TT, Kolodner RD, Hombauer H. 2015. New insights into the mechanism of DNA mismatch repair. Chromosoma 124:443–62 [Google Scholar]
  118. Rieder CL, Medema RH. 2009. No way out for tumor cells. Cancer Cell 16:274–75 [Google Scholar]
  119. Roussel MF. 1999. The INK4 family of cell cycle inhibitors in cancer. Oncogene 18:5311–17 [Google Scholar]
  120. Sadasivam S, DeCaprio JA. 2013. The DREAM complex: master coordinator of cell cycle–dependent gene expression. Nat. Rev. Cancer 13:585–95 [Google Scholar]
  121. Sale JE. 2013. Translesion DNA synthesis and mutagenesis in eukaryotes. Cold Spring Harb. Perspect. Biol. 5:a012708 [Google Scholar]
  122. Sherr CJ. 1995. D-type cyclins. Trends Biochem. Sci. 20:187–90 [Google Scholar]
  123. Sherr CJ. 1996. Cancer cell cycles. Science 274:1672–77 [Google Scholar]
  124. Sherr CJ, Beach D, Shapiro GI. 2016. Targeting CDK4 and CDK6: from discovery to therapy. Cancer Discov 6:353–67 [Google Scholar]
  125. Sherr CJ, Roberts JM. 1999. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–12 [Google Scholar]
  126. Shoaib M, Sorensen CS. 2015. Epigenetic deficiencies and replicative stress: driving cancer cells to an early grave. Cancer Cell 28:545–47 [Google Scholar]
  127. Sorensen CS, Syljuasen RG. 2012. Safeguarding genome integrity: The checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication. Nucleic Acids Res 40:477–86 [Google Scholar]
  128. Stacey DW. 2003. Cyclin D1 serves as a cell cycle regulatory switch in actively proliferating cells. Curr. Opin. Cell Biol. 15:158–63 [Google Scholar]
  129. Strebhardt K, Ullrich A. 2006. Targeting polo-like kinase 1 for cancer therapy. Nat. Rev. Cancer 6:321–30 [Google Scholar]
  130. Sudakin V, Chan GK, Yen TJ. 2001. Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2. J. Cell Biol. 154:925–36 [Google Scholar]
  131. Teixeira LK, Reed SI. 2013. Ubiquitin ligases and cell cycle control. Annu. Rev. Biochem. 82:387–414 [Google Scholar]
  132. Toogood PL, Harvey PJ, Repine JT, Sheehan DJ, VanderWel SN. et al. 2005. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J. Med. Chem 482388–406 [Google Scholar]
  133. Trimarchi JM, Lees JA. 2002. Sibling rivalry in the E2F family. Nat. Rev. Mol. Cell. Biol. 3:11–20 [Google Scholar]
  134. Vaites LP, Lee EK, Lian Z, Barbash O, Roy D. et al. 2011. The Fbx4 tumor suppressor regulates cyclin D1 accumulation and prevents neoplastic transformation. Mol. Cell. Biol. 31:4513–23 [Google Scholar]
  135. Van Linden AA, Baturin D, Ford JB, Fosmire SP, Gardner L. et al. 2013. Inhibition of Wee1 sensitizes cancer cells to antimetabolite chemotherapeutics in vitro and in vivo, independent of p53 functionality. Mol. Cancer Ther. 12:2675–84 [Google Scholar]
  136. VanArsdale T, Boshoff C, Arndt KT, Abraham RT. 2015. Molecular pathways: targeting the cyclin D–CDK4/6 axis for cancer treatment. Clin. Cancer Res. 21:2905–10 [Google Scholar]
  137. Velic D, Couturier AM, Ferreira MT, Rodrigue A, Poirier GG. et al. 2015. DNA damage signalling and repair inhibitors: the long-sought-after Achilles’ heel of cancer. Biomolecules 5:3204–59 [Google Scholar]
  138. Vogelstein B, Lane D, Levine AJ. 2000. Surfing the p53 network. Nature 408:307–10 [Google Scholar]
  139. Vousden KH, Prives C. 2005. P53 and prognosis: new insights and further complexity. Cell 120:7–10 [Google Scholar]
  140. Wang Y, Zhang T, Kwiatkowski N, Abraham BJ, Lee TI. et al. 2015. CDK7-dependent transcriptional addiction in triple-negative breast cancer. Cell 163:174–86 [Google Scholar]
  141. Watanabe S, Watanabe K, Akimov V, Bartkova J, Blagoev B. et al. 2013. JMJD1C demethylates MDC1 to regulate the RNF8 and BRCA1-mediated chromatin response to DNA breaks. Nat. Struct. Mol. Biol. 20:1425–33 [Google Scholar]
  142. Weinstein B. 2008. Relevance of the concept of oncogene addiction to hormonal carcinogenesis and molecular targeting in cancer prevention and therapy. Adv. Exp. Med. Biol 6173–13 [Google Scholar]
  143. Wood KW, Cornwell WD, Jackson JR. 2001. Past and future of the mitotic spindle as an oncology target. Curr. Opin. Pharmacol. 1:370–77 [Google Scholar]
  144. Xu G, Chapman JR, Brandsma I, Yuan J, Mistrik M. et al. 2015. REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature 521:541–44 [Google Scholar]
  145. Yeeles JT, Deegan TD, Janska A, Early A, Diffley JF. 2015. Regulated eukaryotic DNA replication origin firing with purified proteins. Nature 519:431–35Demonstrates that origin-dependent initiation of DNA synthesis in vitro with purified replication factors recapitulates in vivo regulation. [Google Scholar]
  146. Zeman MK, Cimprich KA. 2014. Causes and consequences of replication stress. Nat. Cell Biol. 16:2–9 [Google Scholar]
  147. Zhou BB, Bartek J. 2004. Targeting the checkpoint kinases: chemosensitization versus chemoprotection. Nat. Rev. Cancer 4:216–25 [Google Scholar]
  148. Zimmermann M, Lottersberger F, Buonomo SB, Sfeir A, de Lange T. 2013. 53BP1 regulates DSB repair using Rif1 to control 5′ end resection. Science 339:700–4 [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-040716-075628
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Cell Cycle–Targeted Cancer Therapies
Annual Review of Cancer Biology 1, 41 (2017); https://doi.org/10.1146/annurev-cancerbio-040716-075628
/content/journals/10.1146/annurev-cancerbio-040716-075628
/content/journals/10.1146/annurev-cancerbio-040716-075628
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  • Article Type: Review Article

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