Skip to main content
SpringerLink
Log in

Cell Cycle Machinery and Its Alterations in Pancreatic Cancer

  • Living reference work entry
  • First Online:
Pancreatic Cancer

  • 388 Accesses

Abstract

Cancer is a disease of uncontrolled cell proliferation. Sequencing of the pancreatic cancer genome revealed frequent gene alterations that lead to constitutive proliferation signals and loss of the breaking systems. Cancer cells also display defects in the DNA repair systems, which suggest that compromised genome integrity contributes to the tumorigenesis process. These observations explain many of the abnormal behaviors of cancer cells, yet stopping proliferation of cancer cells remains a difficult task.

This chapter will describe misregulation of the cell-cycle machinery in pancreatic cancer and therapeutic options to stop abnormal proliferation. The basic concept of the normal cell cycle will be outlined first, and the mechanisms of DNA repair will be introduced. Next, alterations of the cell cycle and DNA repair systems in pancreatic cancer will be described. Finally, therapeutic opportunities to target the specific alterations in the cell cycle and DNA repair systems in pancreatic cancer will be discussed.

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

Access this chapter

Log in via an institution

Institutional subscriptions

References

  1. Bleichert F, Botchan MR, Berger JM. Mechanisms for initiating cellular DNA replication. Science. 2017;355(6327):811. doi:10.1126/science.aah6317.

    Article  CAS  Google Scholar 

  2. Losada A. Cohesin in cancer: chromosome segregation and beyond. Nat Rev Cancer. 2014;14(6):389–93. doi:10.1038/nrc3743.

    Article  CAS  PubMed  Google Scholar 

  3. Hirano T. Condensin-based chromosome organization from bacteria to vertebrates. Cell. 2016;164(5):847–57. doi:10.1016/j.cell.2016.01.033.

    Article  CAS  PubMed  Google Scholar 

  4. Musacchio A. The molecular biology of spindle assembly checkpoint signaling dynamics. Curr Biol. 2015;25(20):R1002–18. doi:10.1016/j.cub.2015.08.051.

    Article  CAS  PubMed  Google Scholar 

  5. Peters JM. The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol. 2006;7(9):644–56. doi:10.1038/nrm1988.

    Article  CAS  PubMed  Google Scholar 

  6. Fisher RP. The CDK network: linking cycles of cell division and gene expression. Genes Cancer. 2012;3(11–12):731–8. doi:10.1177/1947601912473308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Boutros R, Dozier C, Ducommun B. The when and wheres of CDC25 phosphatases. Curr Opin Cell Biol. 2006;18(2):185–91. doi:10.1016/j.ceb.2006.02.003.

    Article  CAS  PubMed  Google Scholar 

  8. Mazur PK, Herner A, Mello SS, Wirth M, Hausmann S, Sanchez-Rivera FJ, Lofgren SM, Kuschma T, Hahn SA, Vangala D, Trajkovic-Arsic M, Gupta A, Heid I, Noel PB, Braren R, Erkan M, Kleeff J, Sipos B, Sayles LC, Heikenwalder M, Hessmann E, Ellenrieder V, Esposito I, Jacks T, Bradner JE, Khatri P, Sweet-Cordero EA, Attardi LD, Schmid RM, Schneider G, Sage J, Siveke JT. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat Med. 2015;21(10):1163–71. doi:10.1038/nm.3952.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Polager S, Ginsberg D. E2F – at the crossroads of life and death. Trends Cell Biol. 2008;18(11):528–35. doi:10.1016/j.tcb.2008.08.003.

    Article  CAS  PubMed  Google Scholar 

  10. Dick FA, Rubin SM. Molecular mechanisms underlying RB protein function. Nat Rev Mol Cell Biol. 2013;14(5):297–306. doi:10.1038/nrm3567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Talluri S, Dick FA. Regulation of transcription and chromatin structure by pRB: here, there and everywhere. Cell Cycle. 2012;11(17):3189–98. doi:10.4161/cc.21263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071–8. doi:10.1038/nature08467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu S, Shiotani B, Lahiri M, Marechal A, Tse A, Leung CC, Glover JN, Yang XH, Zou L. ATR autophosphorylation as a molecular switch for checkpoint activation. Mol Cell. 2011;43(2):192–202. doi:10.1016/j.molcel.2011.06.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nam EA, Zhao R, Glick GG, Bansbach CE, Friedman DB, Cortez D. Thr-1989 phosphorylation is a marker of active ataxia telangiectasia-mutated and Rad3-related (ATR) kinase. J Biol Chem. 2011;286(33):28707–14. doi:10.1074/jbc.M111.248914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mordes DA, Cortez D. Activation of ATR and related PIKKs. Cell Cycle. 2008;7(18):2809–12. doi:10.4161/cc.7.18.6689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Marechal A, Zou L. DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol. 2013;5(9):a012716. doi:10.1101/cshperspect.a012716.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Iyer DR, Rhind N. The Intra-S checkpoint responses to DNA damage. Genes (Basel). 2017;8(2):74. doi:10.3390/genes8020074.

    Google Scholar 

  18. Costanzo V, Shechter D, Lupardus PJ, Cimprich KA, Gottesman M, Gautier J. An ATR- and Cdc7-dependent DNA damage checkpoint that inhibits initiation of DNA replication. Mol Cell. 2003;11(1):203–13.

    Article  CAS  PubMed  Google Scholar 

  19. Heffernan TP, Unsal-Kacmaz K, Heinloth AN, Simpson DA, Paules RS, Sancar A, Cordeiro-Stone M, Kaufmann WK. Cdc7-Dbf4 and the human S checkpoint response to UVC. J Biol Chem. 2007;282(13):9458–68. doi:10.1074/jbc.M611292200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dai Y, Grant S. New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin Cancer Res. 2010;16(2):376–83. doi:10.1158/1078-0432.CCR-09-1029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shaltiel IA, Krenning L, Bruinsma W, Medema RH. The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle. J Cell Sci. 2015;128(4):607–20. doi:10.1242/jcs.163766.

    Article  CAS  PubMed  Google Scholar 

  22. Sorensen CS, Syljuasen RG. Safeguarding genome integrity: the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication. Nucleic Acids Res. 2012;40(2):477–86. doi:10.1093/nar/gkr697.

    Article  CAS  PubMed  Google Scholar 

  23. Vitale I, Galluzzi L, Castedo M, Kroemer G. Mitotic catastrophe: a mechanism for avoiding genomic instability. Nat Rev Mol Cell Biol. 2011;12(6):385–92. doi:10.1038/nrm3115.

    Article  CAS  PubMed  Google Scholar 

  24. Escribano-Diaz C, Orthwein A, Fradet-Turcotte A, Xing M, Young JT, Tkac J, Cook MA, Rosebrock AP, Munro M, Canny MD, Xu D, Durocher D. A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol Cell. 2013;49(5):872–83. doi:10.1016/j.molcel.2013.01.001.

    Article  CAS  PubMed  Google Scholar 

  25. Chiruvella KK, Liang Z, Wilson TE. Repair of double-strand breaks by end joining. Cold Spring Harb Perspect Biol. 2013;5(5):a012757. doi:10.1101/cshperspect.a012757.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Witkiewicz AK, McMillan EA, Balaji U, Baek G, Lin WC, Mansour J, Mollaee M, Wagner KU, Koduru P, Yopp A, Choti MA, Yeo CJ, McCue P, White MA, Knudsen ES. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun. 2015;6:6744. doi:10.1038/ncomms7744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Petersen GM. Familial Pancreatic Adenocarcinoma. Hematol Oncol Clin North Am. 2015;29(4):641–53. doi:10.1016/j.hoc.2015.04.007.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, Johns AL, Miller D, Nones K, Quek K, Quinn MC, Robertson AJ, Fadlullah MZ, Bruxner TJ, Christ AN, Harliwong I, Idrisoglu S, Manning S, Nourse C, Nourbakhsh E, Wani S, Wilson PJ, Markham E, Cloonan N, Anderson MJ, Fink JL, Holmes O, Kazakoff SH, Leonard C, Newell F, Poudel B, Song S, Taylor D, Waddell N, Wood S, Xu Q, Wu J, Pinese M, Cowley MJ, Lee HC, Jones MD, Nagrial AM, Humphris J, Chantrill LA, Chin V, Steinmann AM, Mawson A, Humphrey ES, Colvin EK, Chou A, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Pettitt JA, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Jamieson NB, Graham JS, Niclou SP, Bjerkvig R, Grutzmann R, Aust D, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Falconi M, Zamboni G, Tortora G, Tempero MA, Australian Pancreatic Cancer Genome Initiative, Gill AJ, Eshleman JR, Pilarsky C, Scarpa A, Musgrove EA, Pearson JV, Biankin AV, Grimmond SM. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518(7540):495–501. doi:10.1038/nature14169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC, Nourse C, Murtaugh LC, Harliwong I, Idrisoglu S, Manning S, Nourbakhsh E, Wani S, Fink L, Holmes O, Chin V, Anderson MJ, Kazakoff S, Leonard C, Newell F, Waddell N, Wood S, Xu Q, Wilson PJ, Cloonan N, Kassahn KS, Taylor D, Quek K, Robertson A, Pantano L, Mincarelli L, Sanchez LN, Evers L, Wu J, Pinese M, Cowley MJ, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chantrill LA, Mawson A, Humphris J, Chou A, Pajic M, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Lovell JA, Merrett ND, Toon CW, Epari K, Nguyen NQ, Barbour A, Zeps N, Moran-Jones K, Jamieson NB, Graham JS, Duthie F, Oien K, Hair J, Grutzmann R, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Rusev B, Capelli P, Salvia R, Tortora G, Mukhopadhyay D, Petersen GM, Australian Pancreatic Cancer Genome Initiative, Munzy DM, Fisher WE, Karim SA, Eshleman JR, Hruban RH, Pilarsky C, Morton JP, Sansom OJ, Scarpa A, Musgrove EA, Bailey UM, Hofmann O, Sutherland RL, Wheeler DA, Gill AJ, Gibbs RA, Pearson JV, Waddell N, Biankin AV, Grimmond SM. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531(7592):47–52. doi:10.1038/nature16965.

    Article  CAS  PubMed  Google Scholar 

  30. Makohon-Moore A, Iacobuzio-Donahue CA. Pancreatic cancer biology and genetics from an evolutionary perspective. Nat Rev Cancer. 2016;16(9):553–65. doi:10.1038/nrc.2016.66.

    Article  CAS  PubMed  Google Scholar 

  31. Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet. 1994;8(1):27–32. doi:10.1038/ng0994-27.

    Article  CAS  PubMed  Google Scholar 

  32. Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, Moskaluk CA, Hahn SA, Schwarte-Waldhoff I, Schmiegel W, Baylin SB, Kern SE, Herman JG. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res. 1997;57(15):3126–30.

    CAS  PubMed  Google Scholar 

  33. Schleger C, Verbeke C, Hildenbrand R, Zentgraf H, Bleyl U. c-MYC activation in primary and metastatic ductal adenocarcinoma of the pancreas: incidence, mechanisms, and clinical significance. Mod Pathol. 2002;15(4):462–9. doi:10.1038/modpathol.3880547.

    Article  CAS  PubMed  Google Scholar 

  34. Kleeff J, Ishiwata T, Friess H, Buchler MW, Israel MA, Korc M. The helix-loop-helix protein Id2 is overexpressed in human pancreatic cancer. Cancer Res. 1998;58(17):3769–72.

    CAS  PubMed  Google Scholar 

  35. Maruyama H, Kleeff J, Wildi S, Friess H, Buchler MW, Israel MA, Korc M. Id-1 and Id-2 are overexpressed in pancreatic cancer and in dysplastic lesions in chronic pancreatitis. Am J Pathol. 1999;155(3):815–22. doi:10.1016/S0002-9440(10)65180-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lee SH, Hao E, Kiselyuk A, Shapiro J, Shields DJ, Lowy A, Levine F, Itkin-Ansari P. The Id3/E47 axis mediates cell-cycle control in human pancreatic ducts and adenocarcinoma. Mol Cancer Res. 2011;9(6):782–90. doi:10.1158/1541-7786.MCR-10-0535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yachida S, White CM, Naito Y, Zhong Y, Brosnan JA, Macgregor-Das AM, Morgan RA, Saunders T, Laheru DA, Herman JM, Hruban RH, Klein AP, Jones S, Velculescu V, Wolfgang CL, Iacobuzio-Donahue CA. Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors. Clin Cancer Res. 2012;18(22):6339–47. doi:10.1158/1078-0432.CCR-12-1215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Di Agostino S, Strano S, Emiliozzi V, Zerbini V, Mottolese M, Sacchi A, Blandino G, Piaggio G. Gain of function of mutant p53: the mutant p53/NF-Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation. Cancer Cell. 2006;10(3):191–202. doi:10.1016/j.ccr.2006.08.013.

    Article  PubMed  Google Scholar 

  39. Morton JP, Timpson P, Karim SA, Ridgway RA, Athineos D, Doyle B, Jamieson NB, Oien KA, Lowy AM, Brunton VG, Frame MC, Evans TR, Sansom OJ. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc Natl Acad Sci USA. 2010;107(1):246–51. doi:10.1073/pnas.0908428107.

    Article  CAS  PubMed  Google Scholar 

  40. Weissmueller S, Manchado E, Saborowski M, Morris JP, Wagenblast E, Davis CA, Moon SH, Pfister NT, Tschaharganeh DF, Kitzing T, Aust D, Markert EK, Wu J, Grimmond SM, Pilarsky C, Prives C, Biankin AV, Lowe SW. Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor beta signaling. Cell. 2014;157(2):382–94. doi:10.1016/j.cell.2014.01.066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Holter S, Borgida A, Dodd A, Grant R, Semotiuk K, Hedley D, Dhani N, Narod S, Akbari M, Moore M, Gallinger S. Germline BRCA mutations in a large clinic-based cohort of patients with Pancreatic Adenocarcinoma. J Clin Oncol. 2015;33(28):3124–9. doi:10.1200/JCO.2014.59.7401.

    Article  CAS  PubMed  Google Scholar 

  42. Iqbal J, Ragone A, Lubinski J, Lynch HT, Moller P, Ghadirian P, Foulkes WD, Armel S, Eisen A, Neuhausen SL, Senter L, Singer CF, Ainsworth P, Kim-Sing C, Tung N, Friedman E, Llacuachaqui M, Ping S, Narod SA, Hereditary Breast Cancer Study Group. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer. 2012;107(12):2005–9. doi:10.1038/bjc.2012.483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, Lin JC, Palmisano E, Brune K, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Parmigiani G, Kern SE, Velculescu VE, Kinzler KW, Vogelstein B, Eshleman JR, Goggins M, Klein AP. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324(5924):217. doi:10.1126/science.1171202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lal G, Liu G, Schmocker B, Kaurah P, Ozcelik H, Narod SA, Redston M, Gallinger S. Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations. Cancer Res. 2000;60(2):409–16.

    CAS  PubMed  Google Scholar 

  45. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Borresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjord JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Jager N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, Lopez-Otin C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdes-Mas R, van Buuren MM, van ‘t Veer L, Vincent-Salomon A, Waddell N, Yates LR, Australian Pancreatic Cancer Genome Initiative, ICGC Breast Cancer Consortium, ICGC MMML-Seq Consortium, ICGC PedBrain, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–21. doi:10.1038/nature12477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Shakya R, Reid LJ, Reczek CR, Cole F, Egli D, Lin CS, deRooij DG, Hirsch S, Ravi K, Hicks JB, Szabolcs M, Jasin M, Baer R, Ludwig T. BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science. 2011;334(6055):525–8. doi:10.1126/science.1209909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Skoulidis F, Cassidy LD, Pisupati V, Jonasson JG, Bjarnason H, Eyfjord JE, Karreth FA, Lim M, Barber LM, Clatworthy SA, Davies SE, Olive KP, Tuveson DA, Venkitaraman AR. Germline Brca2 heterozygosity promotes Kras(G12D) -driven carcinogenesis in a murine model of familial pancreatic cancer. Cancer Cell. 2010;18(5):499–509. doi:10.1016/j.ccr.2010.10.015.

    Article  CAS  PubMed  Google Scholar 

  48. Ying H, Dey P, Yao W, Kimmelman AC, Draetta GF, Maitra A, DePinho RA. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2016;30(4):355–85. doi:10.1101/gad.275776.115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J, Bachet JB, Khemissa-Akouz F, Pere-Verge D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M, Groupe Tumeurs Digestives of Unicancer, Intergroup PRODIGE. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25. doi:10.1056/NEJMoa1011923.

    Article  CAS  PubMed  Google Scholar 

  50. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–703. doi:10.1056/NEJMoa1304369.

    Article  Google Scholar 

  51. Garrido-Laguna I, Hidalgo M. Pancreatic cancer: from state-of-the-art treatments to promising novel therapies. Nat Rev Clin Oncol. 2015;12(6):319–34. doi:10.1038/nrclinonc.2015.53.

    Article  CAS  PubMed  Google Scholar 

  52. Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. Lancet. 2016;388(10039):73–85. doi:10.1016/S0140-6736(16)00141-0.

    Article  CAS  PubMed  Google Scholar 

  53. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015;14(2):130–46. doi:10.1038/nrd4504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol. 2016;13(7):417–30. doi:10.1038/nrclinonc.2016.26.

    Article  PubMed  Google Scholar 

  55. Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, Greninger P, Thompson IR, Luo X, Soares J, Liu Q, Iorio F, Surdez D, Chen L, Milano RJ, Bignell GR, Tam AT, Davies H, Stevenson JA, Barthorpe S, Lutz SR, Kogera F, Lawrence K, McLaren-Douglas A, Mitropoulos X, Mironenko T, Thi H, Richardson L, Zhou W, Jewitt F, Zhang T, O’Brien P, Boisvert JL, Price S, Hur W, Yang W, Deng X, Butler A, Choi HG, Chang JW, Baselga J, Stamenkovic I, Engelman JA, Sharma SV, Delattre O, Saez-Rodriguez J, Gray NS, Settleman J, Futreal PA, Haber DA, Stratton MR, Ramaswamy S, McDermott U, Benes CH. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483(7391):570–5. doi:10.1038/nature11005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Heilmann AM, Perera RM, Ecker V, Nicolay BN, Bardeesy N, Benes CH, Dyson NJ. CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers. Cancer Res. 2014;74(14):3947–58. doi:10.1158/0008-5472.CAN-13-2923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Franco J, Witkiewicz AK, Knudsen ES. CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer. Oncotarget. 2014;5(15):6512–25. doi:10.18632/oncotarget.2270.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Witkiewicz AK, Borja NA, Franco J, Brody JR, Yeo CJ, Mansour J, Choti MA, McCue P, Knudsen ES. Selective impact of CDK4/6 suppression on patient-derived models of pancreatic cancer. Oncotarget. 2015;6(18):15788–801. doi:10.18632/oncotarget.3819.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Franco J, Balaji U, Freinkman E, Witkiewicz AK, Knudsen ES. Metabolic reprogramming of pancreatic cancer mediated by CDK4/6 inhibition elicits unique vulnerabilities. Cell Rep. 2016;14(5):979–90. doi:10.1016/j.celrep.2015.12.094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hessmann E, Johnsen SA, Siveke JT, Ellenrieder V. Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon? Gut. 2017;66(1):168–79. doi:10.1136/gutjnl-2016-312539.

    Article  PubMed  Google Scholar 

  61. Koutsounas I, Giaginis C, Patsouris E, Theocharis S. Current evidence for histone deacetylase inhibitors in pancreatic cancer. World J Gastroenterol. 2013;19(6):813–28. doi:10.3748/wjg.v19.i6.813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Garcia PL, Miller AL, Kreitzburg KM, Council LN, Gamblin TL, Christein JD, Heslin MJ, Arnoletti JP, Richardson JH, Chen D, Hanna CA, Cramer SL, Yang ES, Qi J, Bradner JE, Yoon KJ. The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene. 2016;35(7):833–45. doi:10.1038/onc.2015.126.

    Article  CAS  PubMed  Google Scholar 

  63. Satoh MS, Lindahl T. Role of poly(ADP-ribose) formation in DNA repair. Nature. 1992;356(6367):356–8. doi:10.1038/356356a0.

    Article  CAS  PubMed  Google Scholar 

  64. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913–7. doi:10.1038/nature03443.

    Article  CAS  PubMed  Google Scholar 

  65. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–21. doi:10.1038/nature03445.

    Article  CAS  PubMed  Google Scholar 

  66. Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S, Pommier Y. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res. 2012;72(21):5588–99. doi:10.1158/0008-5472.CAN-12-2753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fogelman DR, Wolff RA, Kopetz S, Javle M, Bradley C, Mok I, Cabanillas F, Abbruzzese JL. Evidence for the efficacy of Iniparib, a PARP-1 inhibitor, in BRCA2-associated pancreatic cancer. Anticancer Res. 2011;31(4):1417–20.

    PubMed  Google Scholar 

  68. Lowery MA, Kelsen DP, Stadler ZK, Yu KH, Janjigian YY, Ludwig E, D’Adamo DR, Salo-Mullen E, Robson ME, Allen PJ, Kurtz RC, O’Reilly EM. An emerging entity: pancreatic adenocarcinoma associated with a known BRCA mutation: clinical descriptors, treatment implications, and future directions. Oncologist. 2011;16(10):1397–402. doi:10.1634/theoncologist.2011-0185.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmana J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244–50. doi:10.1200/JCO.2014.56.2728.

    Article  CAS  PubMed  Google Scholar 

  70. Rajeshkumar NV, De Oliveira E, Ottenhof N, Watters J, Brooks D, Demuth T, Shumway SD, Mizuarai S, Hirai H, Maitra A, Hidalgo M. MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts. Clin Cancer Res. 2011;17(9):2799–806. doi:10.1158/1078-0432.CCR-10-2580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Karnak D, Engelke CG, Parsels LA, Kausar T, Wei DP, Robertson JR, Marsh KB, Davis MA, Zhao LL, Maybaum J, Lawrence TS, Morgan MA. Combined inhibition of wee1 and PARP1/2 for radiosensitization in pancreatic cancer. Clin Cancer Res. 2014;20(19):5085–96. doi:10.1158/1078-0432.Ccr-14-1038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lal S, Zarei M, Chand SN, Dylgjeri E, Mambelli-Lisboa NC, Pishvaian MJ, Yeo CJ, Winter JM, Brody JR. WEE1 inhibition in pancreatic cancer cells is dependent on DNA repair status in a context dependent manner. Sci Rep. 2016;6:33323. doi:10.1038/srep33323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Engelke CG, Parsels LA, Qian Y, Zhang Q, Karnak D, Robertson JR, Tanska DM, Wei D, Davis MA, Parsels JD, Zhao L, Greenson JK, Lawrence TS, Maybaum J, Morgan MA. Sensitization of pancreatic cancer to chemoradiation by the Chk1 inhibitor MK8776. Clin Cancer Res. 2013;19(16):4412–21. doi:10.1158/1078-0432.CCR-12-3748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oncology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA

    Yusuke Kojima, Reeja S. Maskey & Yuichi J. Machida

Authors
  1. Yusuke Kojima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Reeja S. Maskey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuichi J. Machida
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuichi J. Machida .

Editor information

Editors and Affiliations

  1. DMCCMC, University of Liverpool DMCCMC, Liverpool, United Kingdom

    John P. Neoptolemos

  2. Rochester, Minnesota, USA

    Raul Urrutia

  3. Dept. Gastrointestinal Medical Onco, Duke University Medical Center Dept. Gastrointestinal Medical Onco, Durham, North Carolina, USA

    James Abbruzzese

  4. Heidelberg, Germany

    Markus W. Büchler

Section Editor information

  1. GI Research Unit, Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA

    Raul Urrutia

  2. Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany

    M. W. Büchler MD

  3. Department of Surgery, The Royal Liverpool and Broadgreen University Hospitals NHS Trust, Prescot Street, L7 8XP, Liverpool, UK

    John P. Neoptolemos

  4. Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, L69 3GA, Liverpool, UK

    John P. Neoptolemos

  5. NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK

    John P. Neoptolemos

  6. Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany

    Th. Hackert MD

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media LLC

About this entry

Cite this entry

Kojima, Y., Maskey, R.S., Machida, Y.J. (2017). Cell Cycle Machinery and Its Alterations in Pancreatic Cancer. In: Neoptolemos, J., Urrutia, R., Abbruzzese, J., Büchler, M. (eds) Pancreatic Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-6631-8_74-1

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-6631-8_74-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4939-6631-8

  • Online ISBN: 978-1-4939-6631-8

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation