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Classification of PARP Inhibitors Based on PARP Trapping and Catalytic Inhibition, and Rationale for Combinations with Topoisomerase I Inhibitors and Alkylating Agents

  • Junko Murai
  • Yves Pommier
Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D, volume 83)

Abstract

All PARP inhibitors in clinical development (veliparib, olaparib, niraparib, rucaparib, talazoparib) are potent submicromolar competitive NAD+ inhibitors for PARP1 and PARP2, thereby blocking PARylation reactions [i.e. formation of poly(ADPribose) polymers]. In addition, PARP trapping, which determines the anticancer activity of PARP inhibitors as single agents, is drug-specific, and PARP inhibitors can be ranked according to their PARP trapping potency: Talazoparib >> niraparib ˜ olaparib ˜ rucaparib > veliparib. The highly synergistic effects of PARP inhibitors in combination with alkylating agent (temozolomide or methyl methanesulfonate, MMS) and topoisomerase I (Top1) inhibitors (camptothecins and indenoisoquinolines) are well documented. Both classes of drugs induce DNA single-strand breaks sensed by PARP. Yet, the molecular mechanisms of synergy are different. For alkylating agents (temozolomide and MMS), both PARP trapping and PARylation inhibition account for the synergy, whereas for Top1 inhibitors, there is no involvement of PARP trapping and it is PARylation inhibition that deters the coupling of PARP with the repair enzyme, tyrosyl-DNA phosphodiesterase TDP1. In this chapter, we will review the differences between PARP inhibitors and the rationale for choosing among different PARP inhibitors in combination with alkylating agents or Top1 inhibitors.

Keywords

PARP inhibitor Topoisomerase Camptothecin PARP trapping PARP-DNA complex Synthetic lethal Veliparib Niraparib Olaparib Rucaparib Talazoparib 

References

  1. 1.
    Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–917PubMedCrossRefGoogle Scholar
  2. 2.
    Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921PubMedCrossRefGoogle Scholar
  3. 3.
    Javle M, Curtin NJ (2011) The potential for poly (ADP-ribose) polymerase inhibitors in cancer therapy. Ther Adv Med Oncol 3:257–267Google Scholar
  4. 4.
    Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG (2010) PARP inhibition: PARP1 and beyond. Nat Rev Cancer 10:293–301PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Wahlberg E, Karlberg T, Kouznetsova E, Markova N, Macchiarulo A, Thorsell AG, Pol E, Frostell A, Ekblad T, Oncu D et al (2012) Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors. Nat Biotechnol 30:283–288PubMedCrossRefGoogle Scholar
  6. 6.
    Shen Y, Rehman FL, Feng Y, Boshuizen J, Bajrami I, Elliott R, Wang B, Lord CJ, Post LE, Ashworth A (2013) BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clin Cancer Res 19:5003–5015PubMedCrossRefGoogle Scholar
  7. 7.
    Murai J, Huang SY, Das BB, Dexheimer TS, Takeda S, Pommier Y (2012) Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs DNA damage induced by topoisomerases I and II and base alkylation in vertebrate cells. J Biol Chem 287:12848–12857PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Murai J, Huang SY, 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 72:5588–5599PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Murai J, Huang SY, Renaud A, Zhang Y, Ji J, Takeda S, Morris J, Teicher B, Doroshow JH, Pommier Y (2014) Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther 13:433–443Google Scholar
  10. 10.
    Pommier Y (2012) DNA topoisomerases and cancer. Springer & Humana Press, New YorkCrossRefGoogle Scholar
  11. 11.
    Pommier Y, Leo E, Zhang H, Marchand C (2010) DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol 17:421–433PubMedCrossRefGoogle Scholar
  12. 12.
    Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O’Connor MJ et al (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361:123–134PubMedCrossRefGoogle Scholar
  13. 13.
    Satoh MS, Lindahl T (1992) Role of poly(ADP-ribose) formation in DNA repair. Nature 356:356–358PubMedCrossRefGoogle Scholar
  14. 14.
    Langelier MF, Planck JL, Roy S, Pascal JM (2012) Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1. Science 336:728–732PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Burgess M, Puhalla S (2014) BRCA 1/2-mutation related and sporadic breast and ovarian cancers: more alike than different. Front Oncol 4:19PubMedCentralPubMedGoogle Scholar
  16. 16.
    Curtin NJ, Szabo C (2013) Therapeutic applications of PARP inhibitors: anticancer therapy and beyond. Mol Aspects Med 34:1217–1256Google Scholar
  17. 17.
    De Vos M, Schreiber V, Dantzer F (2012) The diverse roles and clinical relevance of PARPs in DNA damage repair: current state of the art. Biochem Pharmacol 84:137–146PubMedCrossRefGoogle Scholar
  18. 18.
    Sordet O, Redon CE, Guirouilh-Barbat J, Smith S, Solier S, Douarre C, Conti C, Nakamura AJ, Das BB, Nicolas E et al (2009) Ataxia telangiectasia mutated activation by transcription- and topoisomerase I-induced DNA double-strand breaks. EMBO Rep 10:887–893PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Davidson D, Wang Y, Aloyz R, Panasci L (2013) The PARP inhibitor ABT-888 synergizes irinotecan treatment of colon cancer cell lines. Invest New Drugs 31:461–468Google Scholar
  20. 20.
    Kummar S, Chen A, Ji J, Zhang Y, Reid JM, Ames M, Jia L, Weil M, Speranza G, Murgo AJ et al (2011) Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. Cancer Res 71:5626–5634PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Shelton JW, Waxweiler TV, Landry J, Gao H, Xu Y, Wang L, El-Rayes B, Shu HK (2013) In vitro and in vivo enhancement of chemoradiation using the oral PARP inhibitor ABT-888 in colorectal cancer cells. Int J Radiat Oncol Biol Phys 86:469–476PubMedCrossRefGoogle Scholar
  22. 22.
    Tahara M, Inoue T, Sato F, Miyakura Y, Horie H, Yasuda Y, Fujii H, Kotake K, Sugano K (2014) The use of Olaparib (AZD2281) potentiates SN-38 cytotoxicity in colon cancer cells by indirect inhibition of Rad51-Mediated repair of DNA double-strand breaks. Mol Cancer Ther 13:1170–1180PubMedCrossRefGoogle Scholar
  23. 23.
    Tentori L, Leonetti C, Scarsella M, Muzi A, Mazzon E, Vergati M, Forini O, Lapidus R, Xu W, Dorio AS et al (2006) Inhibition of poly(ADP-ribose) polymerase prevents irinotecan-induced intestinal damage and enhances irinotecan/temozolomide efficacy against colon carcinoma. FASEB J 20:1709–1711PubMedCrossRefGoogle Scholar
  24. 24.
    Zhang YW, Regairaz M, Seiler JA, Agama KK, Doroshow JH, Pommier Y (2011) Poly(ADP-ribose) polymerase and XPF-ERCC1 participate in distinct pathways for the repair of topoisomerase I-induced DNA damage in mammalian cells. Nucleic Acids Res 39:3607–3620PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Pommier Y (2006) Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer 6:789–802PubMedCrossRefGoogle Scholar
  26. 26.
    Pommier Y (2013) Drugging topoisomerases: lessons and challenges. ACS Chem Biol 8:82–95PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Interthal H, Pouliot JJ, Champoux JJ (2001) The tyrosyl-DNA phosphodiesterase Tdp1 is a member of the phospholipase D superfamily. Proc Natl Acad Sci U S A 98:12009–12014PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Pouliot JJ, Yao KC, Robertson CA, Nash HA (1999) Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes. Science 286:552–555PubMedCrossRefGoogle Scholar
  29. 29.
    Pommier Y, Huang SY, Gao R, Das BB, Murai J, Marchand C (2014) Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2). DNA Repair 19:114–129PubMedCrossRefGoogle Scholar
  30. 30.
    Das BB, Huang SY, Murai J, Rehman I, Ame JC, Sengupta S, Das SK, Majumdar P, Zhang H, Biard D et al (2014) PARP1-TDP1 coupling for the repair of topoisomerase I-induced DNA damage. Nucleic Acids Res 42:4435–4449PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Hamilton NK, Maizels N (2010) MRE11 function in response to topoisomerase poisons is independent of its function in double-strand break repair in Saccharomyces cerevisiae. PloS One 5:e15387PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Hartsuiker E, Neale MJ, Carr AM (2009) Distinct requirements for the Rad32(Mre11) nuclease and Ctp1(CtIP) in the removal of covalently bound topoisomerase I and II from DNA. Mol Cell 33:117–123Google Scholar
  33. 33.
    Nakamura K, Kogame T, Oshiumi H, Shinohara A, Sumitomo Y, Agama K, Pommier Y, Tsutsui KM, Tsutsui K, Hartsuiker E et al (2010) Collaborative action of Brca1 and CtIP in elimination of covalent modifications from double-strand breaks to facilitate subsequent break repair. PLoS Genet 6:e1000828PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Chatterjee S, Cheng MF, Trivedi D, Petzold SJ, Berger NA (1989) Camptothecin hypersensitivity in poly(adenosine diphosphate-ribose) polymerase-deficient cell lines. Cancer Commun 1:389–394PubMedGoogle Scholar
  35. 35.
    Pommier Y, Barcelo JM, Rao VA, Sordet O, Jobson AG, Thibaut L, Miao ZH, Seiler JA, Zhang H, Marchand C et al (2006) Repair of topoisomerase I-mediated DNA damage. Prog Nucleic Acid Res Mol Biol 81:179–229Google Scholar
  36. 36.
    Smith LM, Willmore E, Austin CA, Curtin NJ (2005) The novel poly(ADP-Ribose) polymerase inhibitor, AG14361, sensitizes cells to topoisomerase I poisons by increasing the persistence of DNA strand breaks. Clin Cancer Res 11:8449–8457PubMedCrossRefGoogle Scholar
  37. 37.
    Bowman KJ, Newell DR, Calvert AH, Curtin NJ (2001) Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro. Br J Cancer 84:106–112PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Patel AG, Flatten KS, Schneider PA, Dai NT, McDonald JS, Poirier GG, Kaufmann SH (2012) Enhanced killing of cancer cells by poly(ADP-ribose) polymerase inhibitors and topoisomerase I inhibitors reflects poisoning of both enzymes. J Biol Chem 287:4198–4210PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    El-Khamisy SF, Masutani M, Suzuki H, Caldecott KW (2003) A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage. Nucleic Acids Res 31:5526–5533Google Scholar
  40. 40.
    Plo I, Liao ZY, Barcelo JM, Kohlhagen G, Caldecott KW, Weinfeld M, Pommier Y (2003) Association of XRCC1 and tyrosyl DNA phosphodiesterase (Tdp1) for the repair of topoisomerase I-mediated DNA lesions. DNA Repair 2:1087–1100PubMedCrossRefGoogle Scholar
  41. 41.
    Dexheimer TS, Antony S, Marchand C, Pommier Y (2008) Tyrosyl-DNA phosphodiesterase as a target for anticancer therapy. Anti-cancer Agents Med Chem 8:381–389CrossRefGoogle Scholar
  42. 42.
    Park SY, Cheng YC (2005) Poly(ADP-ribose) polymerase-1 could facilitate the religation of topoisomerase I-linked DNA inhibited by camptothecin. Cancer Res 65:3894–3902PubMedCrossRefGoogle Scholar
  43. 43.
    Ray Chaudhuri A, Hashimoto Y, Herrador R, Neelsen KJ, Fachinetti D, Bermejo R, Cocito A, Costanzo V, Lopes M (2012) Topoisomerase I poisoning results in PARP-mediated replication fork reversal. Nat Struct Mol Biol 19:417–423PubMedCrossRefGoogle Scholar
  44. 44.
    Berti M, Ray Chaudhuri A, Thangavel S, Gomathinayagam S, Kenig S, Vujanovic M, Odreman F, Glatter T, Graziano S, Mendoza-Maldonado R et al (2013) Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nat Struct Mol Biol 20:347–354PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Strumberg D, Pilon AA, Smith M, Hickey R, Malkas L, Pommier Y (2000) Conversion of topoisomerase I cleavage complexes on the leading strand of ribosomal DNA into 5′-phosphorylated DNA double-strand breaks by replication runoff. Mol Cell Biol 20:3977–3987PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Murai J, Zhang Y, Morris J, Ji J, Takeda S, Doroshow JH, Pommier Y (2014) Rationale for Poly(ADP-ribose) Polymerase (PARP) inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition. J Pharmacol Exp Ther 349:408–416PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Schreiber V, Ame JC, Dolle P, Schultz I, Rinaldi B, Fraulob V, Menissier-de Murcia J, de Murcia G (2002) Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 277:23028–23036PubMedCrossRefGoogle Scholar
  48. 48.
    Horton JK, Wilson SH (2013) strategic combination of dna-damaging agent and parp inhibitor results in enhanced cytotoxicity. Front Oncol 3:257PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Kedar PS, Stefanick DF, Horton JK, Wilson SH (2012) Increased PARP-1 association with DNA in alkylation damaged, PARP-inhibited mouse fibroblasts. Mol Cancer Res MCR 10:360–368Google Scholar
  50. 50.
    Hazra TK, Das A, Das S, Choudhury S, Kow YW, Roy R (2007) Oxidative DNA damage repair in mammalian cells: a new perspective. DNA Repair 6:470–480PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Dexheimer TS, Stephen AG, Fivash MJ, Fisher RJ, Pommier Y (2010) The DNA binding and 3′-end preferential activity of human tyrosyl-DNA phosphodiesterase. Nucleic acids Res 38:2444–2452PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Cistulli C, Lavrik OI, Prasad R, Hou E, Wilson SH (2004) AP endonuclease and poly(ADP-ribose) polymerase-1 interact with the same base excision repair intermediate. DNA Repair 3:581–591PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaUSA

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