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PARP Inhibition as a Prototype for Synthetic Lethal Screens

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Target Identification and Validation in Drug Discovery

Part of the book series: Methods in Molecular Biology ((MIMB,volume 986))

Abstract

Although DNA damaging chemotherapy and radiation therapy remain the main stay of current treatments for cancer patient, these therapies usually have toxic side effect and narrow therapeutic window. One of the challenges in cancer drug discovery is how to identify drugs that selectively kill cancer cells while leaving the normal cell intact. Recently, synthetic lethality has been applied to cancer drug discovery in various settings, and has become a promising approach for identifying novel agents for the treatment of cancer. A prototypical example is the synthetic lethal interaction between PARP inhibition and BRCA deficiency. PARP inhibitors represent the most advanced clinical agents targeting specifically DNA repair mechanisms in cancer therapy. In this chapter, I will review the molecular mechanism for this synthetic lethality and the clinical applications for PARP inhibitors. I will also discuss the formats of synthetic lethal screens, current progress on the utilization of these screens, and some of the advantages and challenges of synthetic lethal screens in cancer drug discovery.

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References

  1. Martin GS (2004) The road to Src. Oncogene 23:7910–7917

    Article  PubMed  CAS  Google Scholar 

  2. Bernard WI, Joe A (2008) Oncogene addiction. Cancer Res 68:3077–3080

    Article  Google Scholar 

  3. Leonard G (1993) Synthetic enhancement in gene interaction: a genetic tool come of age. Trends Genet 9:362–366

    Article  Google Scholar 

  4. Lucchesi JC (1968) Synthetic lethality and semi-lethality among functionally related mutations of Drosophila melanogaster. Genetics 59:37–44

    PubMed  CAS  Google Scholar 

  5. Kaelin WG (2005) The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer 5:689–698

    Article  PubMed  CAS  Google Scholar 

  6. Kaelin WG (2009) Synthetic lethality: a framework for the development of wiser cancer therapeutics. Genome Med 1:99

    Article  PubMed  Google Scholar 

  7. Norbury CJ, Hickson ID (2001) Cellular responses to DNA damage. Annu Rev Pharmacol Toxicol 41:367–401

    Article  PubMed  CAS  Google Scholar 

  8. Schreiber V, Dantzer F, Ame JC et al (2006) PolyADP-ribose: novel functions for an old molecule. Nat Rev Mol Cell Biol 7:517–528

    Article  PubMed  CAS  Google Scholar 

  9. Amé JC, Spenlehauer C, de Murcia G (2004) The PARP superfamily. BioEssays 26:882–893

    Article  PubMed  Google Scholar 

  10. Helleday T, Petermann E, Lundin C et al (2008) DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 8:193–204

    Article  PubMed  CAS  Google Scholar 

  11. Amé JC, Rolli V, Schreiber V et al (1999) PARP-2, a novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase. J Biol Chem 274:17860–17868

    Article  PubMed  Google Scholar 

  12. Moynahan ME, Pierce AJ, Jasin M (2001) BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell 7:263–272

    Article  PubMed  CAS  Google Scholar 

  13. Moynahan ME, Chiu JW, Koller BH et al (1999) Brca1 controls homology-directed DNA repair. Mol Cell 4:511–518

    Article  PubMed  CAS  Google Scholar 

  14. Hennessy B, Timms KM, Carey MS et al (2010) Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly ADP ribose polymerase inhibitors in ovarian cancer. J Clin Oncol 28:3570–3576

    Article  PubMed  Google Scholar 

  15. Kwon JS, Daniels MS, Sun CC et al (2010) Preventing future cancers by testing women with ovarian cancer for BRCA mutations. J Clin Oncol 28:675–682

    Article  PubMed  Google Scholar 

  16. Stadler ZK, Salo ME, Patil SM, Pietanza M et al (2012) Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer. Cancer Res 118:493–499

    CAS  Google Scholar 

  17. Farmer H, McCabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921

    Article  PubMed  CAS  Google Scholar 

  18. Bryant HE, Schultz N, Thomas HD et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly ADP-ribose polymerase. Nature 434:913–917

    Article  PubMed  CAS  Google Scholar 

  19. Penning TD (2010) Small-molecule PARP modulators-current status and future therapeutic potential. Cur Opin Drug Discov Dev 13:577–586

    CAS  Google Scholar 

  20. Mendeleyev J, Kirsten E, Hakam A et al (1995) Potential chemotherapeutic activity of 4-iodo-3-nitrobenzamide: metabolic reduction to the 3-nitroso derivative and induction of cell death in tumor cells in culture. Biochem Pharmacol 50:705–714

    Article  PubMed  CAS  Google Scholar 

  21. Liu X, Shi Y, Maag DX et al (2012) Iniparib nonselectively modifies cysteine-containing proteins in tumor cells and is not a bona fide PARP inhibitor. Clin Cancer Res 18:510–523

    Article  PubMed  CAS  Google Scholar 

  22. Tutt A, Robson M, Garber JE et al (2010) Oral polyADP-ribose polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of- concept trial. Lancet 376:235–244

    Article  PubMed  CAS  Google Scholar 

  23. Audeh MW, Carmichael J, Penson RT et al (2010) Oral polyADP-ribose polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of- concept trial. Lancet 376:245–251

    Article  PubMed  CAS  Google Scholar 

  24. Gelmon KA, Tischkowitz M, Mackay H et al (2011) Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 12:852–861

    Article  PubMed  CAS  Google Scholar 

  25. Kaye SB, Lubinski J, Matulonis U et al (2012) Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 30:372–379

    Article  PubMed  CAS  Google Scholar 

  26. Schelman WR, Sandhu SK, Moreno GV et al (2011) First-in-human trial of a poly(ADP)-ribose polymerase (PARP) inhibitor MK-4827 in advanced cancer patients with antitumor activity in BRCA-deficient tumors and sporadic ovarian cancers (soc). J Clin Oncol 29:abstr 3102

    Google Scholar 

  27. Isakoff S, Overmoyer B, Tung N et al (2010) A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer. J Clin Oncol 28:abstr 1019

    Google Scholar 

  28. Ibragimova I, Cairns P (2011) Assays for hypermethylation of the BRCA1 gene promoter in tumor cells to predict sensitivity to PARP-inhibitor therapy. Methods Mol Biol 780:277–291

    Article  PubMed  CAS  Google Scholar 

  29. Drew Y, Mulligan EA, Vong WT et al (2011) Therapeutic potential of polyADP-ribose polymerase inhibitor AG014699 in human cancers with mutated or methylated BRCA1 or BRCA2. J Nat Cancer Ins 103:334–346

    Article  CAS  Google Scholar 

  30. Johnson N, Li Y, Chen ZE et al (2011) Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. Nat Med 17:875–882

    Article  PubMed  CAS  Google Scholar 

  31. Krawczyk PM, Eppink B, Essers J et al (2011) Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly ADP-ribose polymerase-1 inhibition. Proc Natl Acad Sci USA 108:9851–9856

    Article  PubMed  CAS  Google Scholar 

  32. Chan N, Pires IM, Bencokova Z et al (2010) Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment. Cancer Res 70:8045–8054

    Article  PubMed  CAS  Google Scholar 

  33. Shen WH, Balajee AS, Wang J et al (2007) Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128:157–170

    Article  PubMed  CAS  Google Scholar 

  34. Mendes P, Ana M, Martin SA et al (2009) Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med 1:315–322

    Article  Google Scholar 

  35. Buisson R, Dion C, Anne M et al (2010) Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. Nat Struct Mol Biol 17:1247–1254

    Article  PubMed  CAS  Google Scholar 

  36. Rodriguez C, Hughes DL, Vallès H et al (2004) Amplification of the BRCA2 pathway gene EMSY in sporadic breast cancer is related to negative outcome. Clin Cancer Res 10:5785–5791

    Article  PubMed  CAS  Google Scholar 

  37. Hartwell LH, Szankasi P, Roberts CJ et al (1997) Integrating genetic approaches into the discovery of anticancer drugs. Science 278:1064–1068

    Article  PubMed  CAS  Google Scholar 

  38. Turcotte S, Chan DA, Sutphin PD et al (2008) A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. Cancer Cell 14:90–102

    Article  PubMed  CAS  Google Scholar 

  39. Torrance CJ, Agrawal V, Vogelstein B et al (2001) Use of isogenic human cancer cells for high-throughput screening and drug discovery. Nat Biotechnol 19:940–945

    Article  PubMed  CAS  Google Scholar 

  40. Shaw AT, Winslow MM, Magendantz M et al (2011) Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress. Proc Natl Acad Sci USA 108:8773–8778

    Article  PubMed  CAS  Google Scholar 

  41. Dolma S, Lessnick SL, Hahn WC et al (2003) Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 3:285–296

    Article  PubMed  CAS  Google Scholar 

  42. Luo J, Emanuele MJ, Li D et al (2009) A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137:835–848

    Article  PubMed  CAS  Google Scholar 

  43. Scholl C, Fröhling S, Dunn IF et al (2009) Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 137:821–834

    Article  PubMed  CAS  Google Scholar 

  44. Puyol M, Martín A, Dubus P et al (2010) A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 18:63–73

    Article  PubMed  CAS  Google Scholar 

  45. Bommi RA, Almeciga I, Sawyer J et al (2008) Kinase requirements in human cells: III altered kinase requirements in VHL−/− cancer cells detected in a pilot synthetic lethal screen. Proc Natl Acad Sci USA 105:16484–16489

    Google Scholar 

  46. Martin SA, Hewish M, Sims D et al (2011) Parallel high-throughput RNA interference screens identify PINK1 as a potential therapeutic target for the treatment of DNA mismatch repair-deficient cancers. Cancer Res 71:1836–1848

    Article  PubMed  CAS  Google Scholar 

  47. Brough R, Frankum JR, Sims D et al (2011) Functional viability profiles of breast cancer. Cancer Discov 1:260–273

    Article  PubMed  CAS  Google Scholar 

  48. Babij C, Zhang Y, Kurzeja RJ et al (2011) STK33 kinase activity is nonessential in KRAS-dependent cancer cells. Cancer Res 71:5818–5826

    Article  PubMed  CAS  Google Scholar 

  49. Frohling S, Scholl C (2011) STK33 kinase is not essential in KRAS-dependent cells-letter. Cancer Res 71:7716

    Article  PubMed  Google Scholar 

  50. Weiss WA, Taylor SS, Shokat KM (2007) Recognizing and exploiting differences between RNAi and small-molecule inhibitors. Nat Chem Biol 3:739–744

    Article  PubMed  CAS  Google Scholar 

  51. Wiltshire TD, Lovejoy CA, Wang T et al (2010) Sensitivity to polyADP-ribose polymerase PARP inhibition identifies ubiquitin-specific peptidase 11 USP11 as a regulator of DNA double-strand break repair. J Biol Chem 285:14565–14571

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

I would like to thank Drs. Alexander Shoemaker, Eric Johnson, and Gui-dong Zhu for critically reading the manuscript.

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Authors and Affiliations

  1. Cancer Research, Abbott Laboratories, Abbott Park, IL, USA

    Xuesong Liu

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  1. Xuesong Liu
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Editors and Affiliations

  1. Director, Department of Pharmacology, Boehringer Ingelheim RCV GmbH & Co KG, N/A, Vienna, N/A, Austria

    Jurgen Moll

  2. Project and Team Leader, Cell Biology, Nerviano Medical Sciences, Viale Pasteur 10, Nerviano, 20014, Milano, Italy

    Riccardo Colombo

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Liu, X. (2013). PARP Inhibition as a Prototype for Synthetic Lethal Screens. In: Moll, J., Colombo, R. (eds) Target Identification and Validation in Drug Discovery. Methods in Molecular Biology, vol 986. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-311-4_9

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  • DOI: https://doi.org/10.1007/978-1-62703-311-4_9

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-310-7

  • Online ISBN: 978-1-62703-311-4

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