Skip to main content
SpringerLink
Log in

Disruption of DNA Repair by Cell Cycle and Transcriptional CDK Inhibition

  • Chapter
  • First Online:
PARP Inhibitors for Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D,volume 83))

  • 1682 Accesses

Abstract

The eukaryotic cell cycle is a tightly regulated series of events coordinated by the periodic activation of members of the cyclin dependent kinases (CDK) family. In addition, a subset of CDK family members play critical roles in transcriptional regulation. Dysregulation of CDK activity by a variety of genetic and epigenetic mechanisms is universally observed in cancer and is thought to be a primary driving force in carcinogenesis, such that there has been longstanding interest in targeting CDKs for cancer therapy.

Along with orchestrating the cell cycle and transcriptional events, CDKs have also been directly implicated in the DNA damage response. CDK activity governs cell cycle phase and thus indirectly affects double strand break (DSB) repair pathway choice. Recent evidence also directly implicates CDKs 1 and 2 in homologous recombination DNA repair (HRR) since their activities are crucial at early stages of the repair pathway. These findings suggest that CDK inhibition may not only address aberrant cell proliferation, but may also sensitize cells to a variety of DNA damaging agents as well as PARP inhibition.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Meyerson M, Enders GH, Wu CL, Su LK, Gorka C, Nelson C, Harlow E, Tsai LH (1992) A family of human cdc2-related protein kinases. EMBO J 11:2909–2917

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Malumbres M, Barbacid M (2005) Mammalian cyclin-dependent kinases. Trends Biochem Sci 30(11):630–641. doi:10.1016/j.tibs.2005.09.005

    Article  CAS  PubMed  Google Scholar 

  3. Pines J (1994) The cell cycle kinases. Semin Cancer Biol 5(4):305–313

    CAS  PubMed  Google Scholar 

  4. Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9(3):153–166

    Article  CAS  PubMed  Google Scholar 

  5. Malumbres M, Harlow E, Hunt T, Hunter T, Lahti JM, Manning G, Morgan DO, Tsai L-H, Wolgemuth DJ (2009) Cyclin-dependent kinases: a family portrait. Nat Cell Biol 11(11):1275–1276. doi:http://www.nature.com/ncb/journal/v11/n11/suppinfo/ncb1109-1275_S1.html

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Sausville EA, Zaharevitz D, Gussio R, Meijer L, Louarn-Leost M, Kunick C, Schultz R, Lahusen T, Headlee D, Stinson S, Arbuck SG, Senderowicz A (1999) Cyclin-dependent kinases: initial approaches to exploit a novel therapeutic target. Pharmacol Ther 82(2–3):285–292

    Article  CAS  PubMed  Google Scholar 

  7. Geng Y, Eaton EN, Picon M, Roberts JM, Lundberg AS, Gifford A, Sardet C, Weinberg RA (1996) Regulation of cyclin E transcription by E2Fs and retinoblastoma protein. Oncogene 12:1173–1180

    CAS  PubMed  Google Scholar 

  8. Lundberg AS, R.A. W (1998) Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol Cell Biol 18:753–761

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Harbour JW, Luo RX, Dei Santi A, Postigo AA, Dean DC (1999) Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 98(6):859–869

    Article  CAS  PubMed  Google Scholar 

  10. Harbour JW, Dean DC (2000) The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev 14(19):2393–2409

    Article  CAS  PubMed  Google Scholar 

  11. Ewen ME (1994) The cell cycle and the retinoblastoma protein family. Cancer Metastasis Rev 13:45–66

    Article  CAS  PubMed  Google Scholar 

  12. Ma Y, Cress D, Haura EB (2003) Flavopiridol-induced apoptosis is mediated through up-regulation of E2F-1 and repression of Mcl-1. Mol Cancer Ther 2:73–81

    CAS  PubMed  Google Scholar 

  13. Jiang J, Matranga CB, Cai D, Latham VM, Zhang X, Lowell AM, Martelli F, Shapiro GI (2003) Flavopiridol-induced apoptosis during S phase requires E2F-1 and inhibition of cyclin A-dependent kinase activity. Cancer Res 63:7410–7422

    CAS  PubMed  Google Scholar 

  14. Krek W, Ewen ME, Shirodkar S, Arany Z, Kaelin WG Jr, Livingston DM (1994) Negative regulation of the growth-promoting transcription factor E2F-1 by a stably bound cyclin A-dependent protein kinase. Cell 78:161–172

    Article  CAS  PubMed  Google Scholar 

  15. Dynlacht BD, Flores O, Lees JA, Harlow E (1994) Differential regulation of E2F transactivation by cyclin-cdk2 complexes. Genes Dev 8:1772–1786

    Article  CAS  PubMed  Google Scholar 

  16. Xu M, Sheppard KA, Peng CY, Yee AS, Piwinica-Worms H (1994) Cyclin A/Cdk2 binds directly to E2F-1 and inhibits the DNA-binding activity of E2F-1/DP-1 by phosphorylation. Mol Cell Biol 14:8420–8431

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Chen Y-NP, Sharma SK, Ramsey TM, Jiang L, Martin MS, Baker K, Adams PD, Bair KW, Kaelin WG (1999) Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists. Proc Natl Acad Sci U S A 96(8):4325–4329. doi:10.1073/pnas.96.8.4325

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Ubersax JA, Woodbury EL, Quang PN, Paraz M, Blethrow JD, Shah K, Shokat KM, Morgan DO (2003) Targets of the cyclin-dependent kinase Cdk1. Nature 425(6960):859–864. http://www.nature.com/nature/journal/v425/n6960/suppinfo/nature02062_S1.html

    Article  CAS  PubMed  Google Scholar 

  19. Chi Y, Welcker M, Hizli AA, Posakony JJ, Aebersold R, Clurman BE (2008) Identification of CDK2 substrates in human cell lysates. Genome Biol 9(10):R149. doi:10.1186/gb-2008–9-10-r149

    Article  PubMed Central  PubMed  Google Scholar 

  20. Sherr CJ, Roberts, JM (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 9:1149–1163

    Article  CAS  PubMed  Google Scholar 

  21. Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512

    Article  CAS  PubMed  Google Scholar 

  22. Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, Jessup JM, Pagano M (1997) Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med 3(2):231–234

    Article  CAS  PubMed  Google Scholar 

  23. Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF, Rolfe M (1995) Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 269(5224):682–685

    Article  CAS  PubMed  Google Scholar 

  24. Hu X, Bryington M, Fisher AB, Liang X, Zhang X, Cui D, Datta I, Zuckerman KS (2002) Ubiquitin/proteasome-dependent degradation of D-type cyclins is linked to tumor necrosis factor-induced cell cycle arrest. J Biol Chem 277(19):16528–16537. doi:10.1074/jbc.M109929200

    Article  CAS  PubMed  Google Scholar 

  25. Akoulitchev S, Makela TP, Weinberg RA, Reinberg D (1995) Requirement for TFIIH kinase activity in transcription by RNA polymerase II. Nature 377(6549):557–560

    Article  CAS  PubMed  Google Scholar 

  26. Marshall NF, Peng J, Xie Z, Price DH (1996) Control of RNA polymerase II elongation potential by a novel carboxyl-terminal domain kinase. J Biol Chem 271(43):27176–27183

    Article  CAS  PubMed  Google Scholar 

  27. Peterlin BM, Price DH (2006) Controlling the elongation phase of transcription with P-TEFb. Mol Cell 23(3):297–305

    Article  CAS  PubMed  Google Scholar 

  28. Ni Z, Schwartz BE, Werner J, Suarez JR, Lis JT (2004) Coordination of transcription, RNA processing, and surveillance by P-TEFb kinase on heat shock genes. Mol Cell 13(1):55–65

    Article  CAS  PubMed  Google Scholar 

  29. Adamczewski JP, Rossignol M, Tassan JP, Nigg EA, Moncollin V, Egly JM (1996) MAT1, cdk7 and cyclin H form a kinase complex which is UV light-sensitive upon association with TFIIH. EMBO J 15(8):1877–1884

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Deshpande A, Sicinski P, Hinds PW (2005) Cyclins and cdks in development and cancer: a perspective. Oncogene 24(17):2909–2915

    Article  CAS  PubMed  Google Scholar 

  31. Bartek J, Lukas J (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer cell 3(5):421–429

    Article  CAS  PubMed  Google Scholar 

  32. Zhang Y, Qu D, Morris EJ, O’Hare MJ, Callaghan SM, Slack RS, Geller HM, Park DS (2006) The Chk1/Cdc25A pathway as activators of the cell cycle in neuronal death induced by camptothecin. J Neurosci 26(34):8819–8828. doi:10.1523/jneurosci.2593-06.2006 (The official journal of the Society For Neuroscience)

    Article  CAS  PubMed  Google Scholar 

  33. Timofeev O, Cizmecioglu O, Settele F, Kempf T, Hoffmann I (2010) Cdc25 phosphatases are required for timely assembly of CDK1-cyclin B at the G2/M transition. J Biol Chem 285(22):16978–16990. doi:10.1074/jbc.M109.096552

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Sampath D, Shi Z, Plunkett W (2002) Inhibition of cyclin-dependent kinase 2 by the Chk1-Cdc25A pathway during the S-phase checkpoint activated by fludarabine: dysregulation by 7-hydroxystaurosporine. Mol Pharmacol 62(3):680–688

    Article  CAS  PubMed  Google Scholar 

  35. Johnson N, Cai D, Kennedy RD, Pathania S, Arora M, Li YC, D’Andrea AD, Parvin JD, Shapiro GI (2009) Cdk1 participates in BRCA1-dependent S phase checkpoint control in response to DNA damage. Mol Cell 35 (3):327–339

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Jazayeri A, Falck J, Lukas C, Bartek J, Smith GC, Lukas J, Jackson SP (2006) ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol 8(1):37–45

    Article  CAS  PubMed  Google Scholar 

  37. Huertas P, Jackson SP (2009) Human CtIP mediates cell cycle control of DNA end resection and double strand break repair. J Biol Chem 284(14):9558–9565

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Murai J, Huang S-yN, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S, Pommier Y (2012) Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res 72(21):5588–5599. doi:10.1158/0008-5472.can-12-2753

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Ira G, Pellicioli A, Balijja A, Wang X, Fiorani S, Carotenuto W, Liberi G, Bressan D, Wan L, Hollingsworth NM, Haber JE, Foiani M (2004) DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature 431(7011):1011–1017

    Article  CAS  PubMed  Google Scholar 

  40. Myers JS, Zhao R, Xu X, Ham AJ, Cortez D (2007) Cyclin-dependent kinase 2 dependent phosphorylation of ATRIP regulates the G2-M checkpoint response to DNA damage. Cancer Res 67(14):6685–6690

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Deans AJ, Khanna KK, McNees CJ, Mercurio C, Heierhorst J, McArthur GA (2006) Cyclin-dependent kinase 2 functions in normal DNA repair and is a therapeutic target in BRCA1-deficient cancers. Cancer Res 66(16):8219–8226

    Article  CAS  PubMed  Google Scholar 

  42. Johnson N, Shapiro GI (2010) Cyclin-dependent kinases (cdks) and the DNA damage response: rationale for cdk inhibitor–chemotherapy combinations as an anticancer strategy for solid tumors. Expert Opin Ther Targets 14(11):1199–1212. doi:10.1517/14728222.2010.525221

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Tomimatsu N, Mukherjee B, Catherine Hardebeck M, Ilcheva M, Vanessa Camacho C, Louise Harris J, Porteus M, Llorente B, Khanna KK, Burma S (2014) Phosphorylation of EXO1 by CDKs 1 and 2 regulates DNA end resection and repair pathway choice. Nat Commun 5:3561. doi:10.1038/ncomms4561

    Article  PubMed Central  PubMed  Google Scholar 

  44. Abraham RT (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 15(17):2177–2196

    Article  CAS  PubMed  Google Scholar 

  45. Anantha RW, Vassin VM, Borowiec JA (2007) Sequential and synergistic modification of human RPA stimulates chromosomal DNA repair. J Biol Chem 282(49):35910–35923

    Article  CAS  PubMed  Google Scholar 

  46. West SC (2003) Molecular views of recombination proteins and their control. Nat Rev Mol Cell Biol 4(6):435–445

    Article  CAS  PubMed  Google Scholar 

  47. Ambrosini G, Seelman SL, Qin LX, Schwartz GK (2008) The cyclin-dependent kinase inhibitor flavopiridol potentiates the effects of topoisomerase I poisons by suppressing Rad51 expression in a p53-dependent manner. Cancer Res 68(7):2312–2320. doi:10.1158/0008-5472.can-07-2395

    Article  CAS  PubMed  Google Scholar 

  48. Esashi F, Christ N, Gannon J, Liu Y, Hunt T, Jasin M, West SC (2005) CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature 434(7033):598–604. doi:10.1038/nature03404

    Article  CAS  PubMed  Google Scholar 

  49. Berthet C, Aleem E, Coppola V, Tessarollo L, Kaldis P (2003) Cdk2 knockout mice are viable. Curr Biol 13(20):1775–1785

    Article  CAS  PubMed  Google Scholar 

  50. Ortega S, Prieto I, Odajima J, Martin A, Dubus P, Sotillo R, Barbero JL, Malumbres M, Barbacid M (2003) Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet 35:25–31

    Article  CAS  PubMed  Google Scholar 

  51. Ruffner H, Jiang W, Craig AG, Hunter T, Verma IM (1999) BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site. Mol Cell Biol 19(7):4843–4854

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Johnson N, Li YC, Walton ZE, Cheng KA, Li D, Rodig SJ, Moreau LA, Unitt C, Bronson RT, Thomas HD, Newell DR, D’Andrea AD, Curtin NJ, Wong KK, Shapiro GI (2011) Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. Nat Med 17(7):875–882

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Santamaria D, Barriere C, Cerqueira A, Hunt S, Tardy C, Newton K, Caceres JF, Dubus P, Malumbres M, Barbacid M (2007) Cdk1 is sufficient to drive the mammalian cell cycle. Nature 448(7155):811–815

    Article  CAS  PubMed  Google Scholar 

  54. Cerqueira A, Santamaria D, Martinez-Pastor B, Cuadrado M, Fernandez-Capetillo O, Barbacid M (2009) Overall Cdk activity modulates the DNA damage response in mammalian cells. J Cell Biol 187(6):773–780

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Dhavan R, Greer PL, Morabito MA, Orlando LR, Tsai LH (2002) The cyclin-dependent kinase 5 activators p35 and p39 interact with the alpha-subunit of Ca2+/calmodulin-dependent protein kinase II and alpha-actinin-1 in a calcium-dependent manner. J Neurosci 22(18):7879–7891 (The official journal of the Society for Neuroscience)

    CAS  PubMed  Google Scholar 

  56. Angelo M, Plattner F, Giese KP (2006) Cyclin-dependent kinase 5 in synaptic plasticity, learning and memory. J Neurochem 99(2):353–370. doi:10.1111/j.1471-4159.2006.04040.x

    Article  CAS  PubMed  Google Scholar 

  57. Turner NC, Lord CJ, Iorns E, Brough R, Swift S, Elliott R, Rayter S, Tutt AN, Ashworth A (2008) A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor. EMBO J 27(9):1368–1377. doi:10.1038/emboj.2008.61

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Sedlacek H, Czech J, Naik R, Kaur G, Worland P, Losiewicz M, Parker B, Carlson B, Smith A, Senderowicz A, Sausville E (1996) Flavopiridol (L86 8275; NSC 649890), a new kinase inhibitor for tumor therapy. Int J Oncol 9(6):1143–1168

    CAS  PubMed  Google Scholar 

  59. Napolitano G, Majello B, Lania L (2002) Role of cyclinT/Cdk9 complex in basal and regulated transcription (review). Int J Oncol 21(1):171–177

    CAS  PubMed  Google Scholar 

  60. Bible KC, Kaufmann SH (1997) Cytotoxic synergy between Flavopiridol and various antineoplastic agents: the importance of sequence of administration. Cancer Res 57:3375–3380

    CAS  PubMed  Google Scholar 

  61. Alonso M, Tamasdan C, Miller DC, Newcomb EW (2003) Flavopiridol induces apoptosis in glioma cell lines independent of retinoblastoma and p53 tumor suppressor pathway alterations by a caspase-independent pathway. Mol Cancer Ther 2(2):139–150

    CAS  PubMed  Google Scholar 

  62. Demidenko ZN, Blagosklonny MV (2004) Flavopiridol induces p53 via initial inhibition of Mdm2 and p21 and, independently of p53, sensitizes apoptosis-reluctant cells to tumor necrosis factor. Cancer Res 64(10):3653–3660

    Article  CAS  PubMed  Google Scholar 

  63. Bartkowiak B, Liu P, Phatnani HP, Fuda NJ, Cooper JJ, Price DH, Adelman K, Lis JT, Greenleaf AL (2010) CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1. Genes Dev 24(20):2303–2316. doi:10.1101/gad.1968210

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Kohoutek J, Blazek D (2012) Cyclin K goes with Cdk12 and Cdk13. Cell Div 7(1):12

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Blazek D, Kohoutek J, Bartholomeeusen K, Johansen E, Hulinkova P, Luo Z, Cimermancic P, Ule J, Peterlin BM (2011) The cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes Dev 25(20):2158–2172. doi:10.1101/gad.16962311

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Blazek D (2012) The cyclin K/Cdk12 complex: an emerging new player in the maintenance of genome stability. Cell Cycle 11(6):1049–1050 (Georgetown, Tex)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Cancer Genome Atlas Research Network (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474(7353):6093re). doi:10.1038/nature10166

    Google Scholar 

  68. Joshi PM, Sutor SL, Huntoon CJ, Karnitz LM (2014) Ovarian cancer-associated mutations disable catalytic activity of CDK12, a kinase that promotes homologous recombination repair and resistance to cisplatin and poly(ADP-ribose) polymerase inhibitors. J Biol Chem 289(13):9247–9253. doi:10.1074/jbc.M114.551143

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Bajrami I, Frankum JR, Konde A, Miller RE, Rehman FL, Brough R, Campbell J, Sims D, Rafiq R, Hooper S, Chen L, Kozarewa I, Assiotis I, Fenwick K, Natrajan R, Lord CJ, Ashworth A (2014) Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity. Cancer Res 74(1):287–297. doi:10.1158/0008-5472.can-13-2541

    Article  CAS  PubMed  Google Scholar 

  70. Scully R, Xie A (2005) In my end is my beginning: control of end resection and DSBR pathway ‘choice’ by cyclin-dependent kinases. Oncogene 24(17):2871–2876

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Chapman JR, Barral P, Vannier JB, Borel V, Steger M, Tomas-Loba A, Sartori AA, Adams IR, Batista FD, Boulton SJ (2013) RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA Double-strand break resection. Mol Cell 49(5):858–871. http://dx.doi.org/10.1016/j.molcel.2013.01.002

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Di Virgilio M, Callen E, Yamane A, Zhang W, Jankovic M, Gitlin AD, Feldhahn N, Resch W, Oliveira TY, Chait BT, Nussenzweig A, Casellas R, Robbiani DF, Nussenzweig MC (2013) Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science 339(6120):711–715. doi:10.1126/science.1230624

    Article  CAS  PubMed  Google Scholar 

  73. Escribano-Díaz C, Orthwein A, Fradet-Turcotte A, Xing M, Young JT, Tkáč J, Cook MA, Rosebrock AP, Munro M, Canny MD, Xu D, Durocher D (2013) A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol Cell 49(5):872–883. doi:http://dx.doi.org/10.1016/j.molcel.2013.01.001

    Article  PubMed  Google Scholar 

  74. 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(6120):700–704. doi:10.1126/science.1231573

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Patel AG, Sarkaria JN, Kaufmann SH (2011) Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Proc Natl Acad Sci U S A 108(8):3406–3411. doi:10.1073/pnas.1013715108

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, Los G, Slamon DJ (2009) PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res (BCR) 11(5):R77. doi:10.1186/bcr2419

    Article  Google Scholar 

  77. Dean JL, Thangavel C, McClendon AK, Reed CA, Knudsen ES (2010) Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene 29(28):4018–4032. doi:10.1038/onc.2010.154

    Article  CAS  PubMed  Google Scholar 

  78. Dean JL, McClendon AK, Knudsen ES (2012) Modification of the DNA damage response by therapeutic CDK4/6 inhibition. J Biol Chem 287(34):29075–29087. doi:10.1074/jbc.M112.365494

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Jirawatnotai S, Hu Y, Michowski W, Elias JE, Becks L, Bienvenu F, Zagozdzon A, Goswami T, Wang YE, Clark AB, Kunkel TA, van Harn T, Xia B, Correll M, Quackenbush J, Livingston DM, Gygi SP, Sicinski P (2011) A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. Nature 474(7350):230–234. doi:10.1038/nature10155

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL (2004) Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 3(11):1427–1438

    CAS  PubMed  Google Scholar 

  81. Tate SC, Cai S, Ajamie RT, Burke T, Beckmann RP, Chan EM, De Dios A, Wishart GN, Gelbert LM, Cronier DM (2014) Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the anti-tumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts. Clin Cancer Res 20(14):3763–3774. doi:10.1158/1078-0432.ccr-13-2846 (An official journal of the American Association for Cancer Research)

    Article  CAS  PubMed  Google Scholar 

  82. Kim S, Loo A, Chopra R, Caponigro G, Huang A, Vora S, Parasuraman S, Howard S, Keen N, Sellers W, Brain C (2013) Abstract PR02: LEE011: an orally bioavailable, selective small molecule inhibitor of CDK4/6–Reactivating Rb in cancer. Mol Cancer Ther 12(11 Supplement):PR02. doi:10.1158/1535-7163.targ-13-pr02

    Article  Google Scholar 

  83. Infante JR, Shapiro GI, Witteveen PO, Gerecitano JF, Ribrag V, Chugh R, Chakraborty A, Matano A, Zhao X, Parasuraman S, Cassier PA (2013) Abstract A276: phase 1 multicenter, open label, dose-escalation study of LEE011, an oral inhibitor of cyclin-dependent kinase 4/6, in patients with advanced solid tumors or lymphomas. Mol Cancer Ther 12(11 Supplement):A276. doi:10.1158/1535-7163.targ-13-a276

    Article  Google Scholar 

  84. Flaherty KT, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, Shaik MN, Wilner KD, O’Dwyer PJ, Schwartz GK (2012) Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res 18(2):568–576. doi:10.1158/1078-0432.ccr-11-0509 (An official journal of the American Association for Cancer Research)

    Article  CAS  PubMed  Google Scholar 

  85. Shapiro GI, Rosen LS, Tolcher AW, Goldman JW, Gandhi L, Papadopoulos KP, Tolaney SM, Beeram M, Rasco DW, Kulanthaivel P, Li Q, Hu T, Cronier D, Chan EM, Flaherty K, Wen PY, Patnaik A (2013) A first-in-human phase I study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer. J Clin Oncol 31

    Google Scholar 

  86. Dickson MA, Tap WD, Keohan ML, D’Angelo SP, Gounder MM, Antonescu CR, Landa J, Qin LX, Rathbone DD, Condy MM, Ustoyev Y, Crago AM, Singer S, Schwartz GK (2013) Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol 31(16):2024–2028. doi:10.1200/jco.2012.46.5476

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Leonard JP, LaCasce AS, Smith MR, Noy A, Chirieac LR, Rodig SJ, Yu JQ, Vallabhajosula S, Schoder H, English P, Neuberg DS, Martin P, Millenson MM, Ely SA, Courtney R, Shaik N, Wilner KD, Randolph S, Van den Abbeele AD, Chen-Kiang SY, Yap JT, Shapiro GI (2012) Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 119(20):4597–4607

    Article  CAS  PubMed  Google Scholar 

  88. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk YV, Thummala AR, Voytko NL, Huang X, Kim ST, Randolph SS, Slamon DJ (2014) Final results of a randomized phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18). AACR Meeting Abstracts, 2014:CT101

    Google Scholar 

  89. Vora S, Kim N, Costa C, Lockerman E, Li X, Chen Y, Cao A, Pinzon-Ortiz M, Liu M, Kim S, Schlegel R, Huang A, Engelman J (2013) Abstract S4–04: overcoming resistance to PI3K inhibitors in PIK3CA mutant breast cancer using CDK4/6 inhibition: results from a combinatorial drug screen. Cancer Res 73(24 Supplement):S4–04. doi:10.1158/0008-5472.sabcs13-s4-04

    Google Scholar 

  90. Kwong LN, Costello JC, Liu H, Jiang S, Helms TL, Langsdorf AE, Jakubosky D, Genovese G, Muller FL, Jeong JH, Bender RP, Chu GC, Flaherty KT, Wargo JA, Collins JJ, Chin L (2012) Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med 18(10):1503–1510. http://www.nature.com/nm/journal/v18/n10/abs/nm.2941.html#supplementary-information

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  91. Parry D, Guzi T, Shanahan F, Davis N, Prabhavalkar D, Wiswell D, Seghezzi W, Paruch K, Dwyer MP, Doll R, Nomeir A, Windsor W, Fischmann T, Wang Y, Oft M, Chen T, Kirschmeier P, Lees EM (2010) Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther 9(8):2344–2353. doi:10.1158/1535-7163.mct-10-0324

    Article  CAS  PubMed  Google Scholar 

  92. Le Tourneau C, Faivre S, Laurence V, Delbaldo C, Vera K, Girre V, Chiao J, Armour S, Frame S, Green SR, Gianella-Borradori A, Dieras V, Raymond E (2010) Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. Eur J Cancer 46(18):3243–3250. doi:10.1016/j.ejca.2010.08.001 (Oxford, England: 1990)

    Article  CAS  PubMed  Google Scholar 

  93. Siemeister G, Lucking U, Wengner AM, Lienau P, Steinke W, Schatz C, Mumberg D, Ziegelbauer K (2012) BAY 1000394, a novel cyclin-dependent kinase inhibitor, with potent antitumor activity in mono- and in combination treatment upon oral application. Mol Cancer Ther 11(10):2265–2273. doi:10.1158/1535-7163.mct-12-0286

    Article  CAS  PubMed  Google Scholar 

  94. Shapiro GI (2006) Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol 24(11):1770–1783. doi:10.1200/jco.2005.03.7689

    Article  CAS  PubMed  Google Scholar 

  95. Johnson SF, Johnson N, Chi D, Primack B, D’Andrea AD, Lim E, Shapiro GI (2013) Abstract 1788: The CDK inhibitor dinaciclib sensitizes triple-negative breast cancer cells to PARP inhibition. Proceedings of the 104th Annual Meeting of the American Association for Cancer Research. Cancer Res 2013

    Google Scholar 

  96. Crescenzi E, Palumbo G, Brady HJ (2005) Roscovitine modulates DNA repair and senescence: implications for combination chemotherapy. Clin Cancer Res (An official journal of the American Association for Cancer Research) 11(22):8158–8171. doi:10.1158/1078-0432.ccr-05-1042

    Article  CAS  PubMed  Google Scholar 

  97. Shah MA, Kortmansky J, Motwani M, Drobnjak M, Gonen M, Yi S, Weyerbacher A, Cordon-Cardo C, Lefkowitz R, Brenner B, O’Reilly E, Saltz L, Tong W, Kelsen DP, Schwartz GK (2005) A phase I clinical trial of the sequential combination of irinotecan followed by flavopiridol. Clin Cancer Res 11(10):3836–3845. doi:10.1158/1078-0432.ccr-04-2651 (An official journal of the American Association for Cancer Research)

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Early Drug Development Center and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Liam Cornell & Geoffrey I. Shapiro

  2. Developmental Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA

    Neil Johnson

Authors
  1. Liam Cornell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Neil Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Geoffrey I. Shapiro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Liam Cornell .

Editor information

Editors and Affiliations

  1. Northern Institute for Cancer Research and Newcastle University Institute for Ageing Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom

    Nicola J. Curtin

  2. CRUK-MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom

    Ricky A. Sharma

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Cornell, L., Johnson, N., Shapiro, G. (2015). Disruption of DNA Repair by Cell Cycle and Transcriptional CDK Inhibition. In: Curtin, N., Sharma, R. (eds) PARP Inhibitors for Cancer Therapy. Cancer Drug Discovery and Development, vol 83. Humana Press, Cham. https://doi.org/10.1007/978-3-319-14151-0_17

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-14151-0_17

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-14150-3

  • Online ISBN: 978-3-319-14151-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation