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Targeting DNA Repair in Anti-Cancer Treatments

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Targeting the DNA Damage Response for Anti-Cancer Therapy

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

Abstract

Treatment of cancer started long before the emergence of modern pharmaceuticals, and over the decades, mankind has tried just about everything to battle this disease. Besides surgery, only a handful of treatments have stood the test of time: ionizing radiation, discovered by Wilhelm Röntgen, and chemotherapy treatments, discovered serendipitously in the release of mustard gas following the bombing of an American cargo ship in Bari (Italy) during the Second World War. Antimetabolites and natural products were also found to have potent anti-cancer effects and much later it was discovered that all the anti-cancer drugs share the same target: DNA. Hence, there is overwhelming evidence that causing DNA damage is an effective way of treating cancer.

DNA was for a long time thought to be highly stable, a prevailing view until Tomas Lindahl discovered the spontaneous decay of DNA (Lindahl and Andersson 1972; Lindahl and Nyberg 1974). As DNA is indispensable for life, Dr. Lindahl hypothesized that there must be a way to repair the DNA and subsequently he identified the first DNA repair protein, a uracil DNA glycosylase (Lindahl 1974). For this discovery he got the 2015 Nobel Prize in Chemistry, which he shared with Drs. Paul Modrich and Aziz Sancar for their discoveries of other DNA repair pathways. Over the years, hundreds of DNA repair proteins have been identified and their individual role has been studied in great biochemical detail (Hoeijmakers 2001).

Although DNA damaging agents dramatically improved cancer survival rates and prolonged life, it was evident early on that cancers relapsed and developed resistance. For clinicians it was clear that the cancer cells somehow escaped the treatments and a likely mechanism was by improving their ability to repair DNA. Hence, a way to decrease the DNA repair capacity of cancer cells has been on the agenda for a long time to improve cancer treatment, in particular in the radiation oncology field. The big issue has always been how to selectively sensitize the cancer cells and not the non-transformed cells?

COI statement: the author is listed inventor of numerous patents targeting DNA repair in cancers and recieves royalty from PARP inhibitor sales.

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References

  • Baell J, Walters MA (2014) Chemistry: chemical con artists foil drug discovery. Nature 513:481–483

    Article  CAS  PubMed  Google Scholar 

  • Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K, Guldberg P, Sehested M, Nesland JM, Lukas C, Orntoft T, Lukas J, Bartek J (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434:864–870

    Article  CAS  PubMed  Google Scholar 

  • Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, Vassiliou LV, Kolettas E, Niforou K, Zoumpourlis VC, Takaoka M, Nakagawa H, Tort F, Fugger K, Johansson F, Sehested M, Andersen CL, Dyrskjot L, Orntoft T, Lukas J et al (2006) Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444:633–637

    Article  CAS  PubMed  Google Scholar 

  • Bester AC, Roniger M, Oren YS, Im MM, Sarni D, Chaoat M, Bensimon A, Zamir G, Shewach DS, Kerem B (2011) Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell 145:435–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boulton S, Pemberton LC, Porteous JK, Curtin NJ, Griffin RJ, Golding BT, Durkacz BW (1995) Potentiation of temozolomide-induced cytotoxicity: a comparative study of the biological effects of poly(ADP-ribose) polymerase inhibitors. Br J Cancer 72:849–856. Order

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 434:913–917

    Article  CAS  PubMed  Google Scholar 

  • Bunting SF, Callen E, Wong N, Chen HT, Polato F, Gunn A, Bothmer A, Feldhahn N, Fernandez-Capetillo O, Cao L, Xu X, Deng CX, Finkel T, Nussenzweig M, Stark JM, Nussenzweig A (2010) 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141:243–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Curtin NJ (2012) DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer 12:801–817

    Article  CAS  PubMed  Google Scholar 

  • Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C, Schurra C, Garre M, Nuciforo PG, Bensimon A, Maestro R, Pelicci PG, d’Adda di Fagagna F (2006) Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444:638–642

    Article  CAS  PubMed  Google Scholar 

  • Durkacz BW, Omidiji O, Gray DA, Shall S (1980) (ADP-ribose)n participates in DNA excision repair. Nature 283:593–596

    Article  CAS  PubMed  Google Scholar 

  • 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 (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921

    Article  CAS  PubMed  Google Scholar 

  • Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O'Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS (2009) Inhibition of poly(ADP-Ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361:123–134

    Article  CAS  PubMed  Google Scholar 

  • Gad H, Koolmeister T, Jemth AS, Eshtad S, Jacques SA, Strom CE, Svensson LM, Schultz N, Lundback T, Einarsdottir BO, Saleh A, Gokturk C, Baranczewski P, Svensson R, Berntsson RP, Gustafsson R, Stromberg K, Sanjiv K, Jacques-Cordonnier MC, Desroses M et al (2014) MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature 508:215–221

    Article  CAS  PubMed  Google Scholar 

  • Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M et al (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366:883–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T, Venere M, Ditullio RA Jr, Kastrinakis NG, Levy B, Kletsas D, Yoneta A, Herlyn M, Kittas C, Halazonetis TD (2005) Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434:907–913

    Article  CAS  PubMed  Google Scholar 

  • Gorrini C, Harris IS, Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12:931–947

    Article  CAS  PubMed  Google Scholar 

  • Griffin RJ, Pemberton LC, Rhodes D, Bleasdale C, Bowman K, Calvert AH, Curtin NJ, Durkacz BW, Newell DR, Porteous JK et al (1995) Novel potent inhibitors of the DNA repair enzyme poly(ADP-ribose)polymerase (PARP). Anticancer Drug Des 10:507–514

    PubMed  CAS  Google Scholar 

  • Halazonetis TD, Gorgoulis VG, Bartek J (2008) An oncogene-induced DNA damage model for cancer development. Science 319:1352–1355

    Article  CAS  Google Scholar 

  • Hartwell LH, Szankasi P, Roberts CJ, Murray AW, Friend SH (1997) Integrating genetic approaches into the discovery of anticancer drugs. Science 278:1064–1068

    Article  CAS  PubMed  Google Scholar 

  • Helleday T (2003) Use of rnai inhibiting parp activtiy for the manufacture of a medicament for the treatment of cancer. patent WO 2005012524r A1

    Google Scholar 

  • Helleday T (2008) Amplifying tumour-specific replication lesions by DNA repair inhibitors–a new era in targeted cancer therapy. Eur J Cancer 44(7):921–927

    Article  CAS  PubMed  Google Scholar 

  • Helleday T (2011) The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol 5:387–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA (2008) DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 8:193–204

    Article  CAS  PubMed  Google Scholar 

  • Hoeijmakers JH (2001) Genome maintenance mechanisms for preventing cancer. Nature 411:366–374

    Article  CAS  PubMed  Google Scholar 

  • Huber KV, Salah E, Radic B, Gridling M, Elkins JM, Stukalov A, Jemth AS, Gokturk C, Sanjiv K, Stromberg K, Pham T, Berglund UW, Colinge J, Bennett KL, Loizou JI, Helleday T, Knapp S, Superti-Furga G (2014) Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. Nature 508:222–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones RM, Mortusewicz O, Afzal I, Lorvellec M, Garcia P, Helleday T, Petermann E (2013) Increased replication initiation and conflicts with transcription underlie Cyclin E-induced replication stress. Oncogene 32:3744–3753

    Article  CAS  PubMed  Google Scholar 

  • Lindahl T (1974) An N-glycosidase from Escherichia coli that releases free uracil from DNA containing deaminated cytosine residues. Proc Natl Acad Sci U S A 71:3649–3653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lindahl T, Andersson A (1972) Rate of chain breakage at apurinic sites in double-stranded deoxyribonucleic acid. Biochemistry 11:3618–3623

    Article  CAS  PubMed  Google Scholar 

  • Lindahl T, Nyberg B (1974) Heat-induced deamination of cytosine residues in deoxyribonucleic acid. Biochemistry 13:3405–3410

    Article  CAS  PubMed  Google Scholar 

  • Lindahl T, Satoh MS, Poirier GG, Klungland A (1995) Post-translational modification of poly(ADP-ribose) polymerase induced by DNA strand breaks. Trends Biochem Sci 20:405–411

    Article  CAS  PubMed  Google Scholar 

  • Ma CX, Janetka JW, Piwnica-Worms H (2010) Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics. Trends Mol Med 17:88–96

    Article  CAS  PubMed  Google Scholar 

  • 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 72:5588–5599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murga M, Campaner S, Lopez-Contreras AJ, Toledo LI, Soria R, Montana MF, D’Artista L, Schleker T, Guerra C, Garcia E, Barbacid M, Hidalgo M, Amati B, Fernandez-Capetillo O (2011) Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nat Struct Mol Biol 18:1331–1335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oikawa A, Tohda H, Kanai M, Miwa M, Sugimura T (1980) Inhibitors of poly(adenosine diphosphate ribose) polymerase induce sister chromatid exchanges. Biochem Biophys Res Commun 97:1311–1316

    Article  CAS  PubMed  Google Scholar 

  • Petrocchi A, Leo E, Reyna NJ, Hamilton MM, Shi X, Parker CA, Mseeh F, Bardenhagen JP, Leonard P, Cross JB, Huang S, Jiang Y, Cardozo M, Draetta G, Marszalek JR, Toniatti C, Jones P, Lewis RT (2016) Identification of potent and selective MTH1 inhibitors. Bioorg Med Chem Lett 26:1503–1507

    Article  CAS  PubMed  Google Scholar 

  • Plummer R, Lorigan P, Steven N, Scott L, Middleton MR, Wilson RH, Mulligan E, Curtin N, Wang D, Dewji R, Abbattista A, Gallo J, Calvert H (2013) A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation. Cancer Chemother Pharmacol 71:1191–1199

    Article  CAS  PubMed  Google Scholar 

  • Purnell MR, Whish WJ (1980) Novel inhibitors of poly(ADP-ribose) synthetase. Biochem J 185:775–777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, Villegas E, Jacquemont C, Farrugia DJ, Couch FJ, Urban N, Taniguchi T (2008) Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451:1116–1120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanjiv K, Hagenkort A, Calderon-Montano JM, Koolmeister T, Reaper PM, Mortusewicz O, Jacques SA, Kuiper RV, Schultz N, Scobie M, Charlton PA, Pollard JR, Berglund UW, Altun M, Helleday T (2016) Cancer-specific synthetic lethality between ATR and CHK1 kinase activities. Cell Rep 14:298–309

    Article  CAS  PubMed  Google Scholar 

  • Shall S (1975) Proceedings: experimental manipulation of the specific activity of poly(ADP-ribose) polymerase. J Biochem 77:2

    Article  Google Scholar 

  • Toledo LI, Murga M, Zur R, Soria R, Rodriguez A, Martinez S, Oyarzabal J, Pastor J, Bischoff JR, Fernandez-Capetillo O (2011) A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat Struct Mol Biol 18:721–727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Warpman Berglund U, Sanjiv K, Gad H, Kalderen C, Koolmeister T, Pham T, Gokturk C, Jafari R, Maddalo G, Seashore-Ludlow B, Chernobrovkin A, Manoilov A, Pateras IS, Rasti A, Jemth AS, Almlof I, Loseva O, Visnes T, Einarsdottir BO, Gaugaz FZ et al (2016) Validation and development of MTH1 inhibitors for treatment of cancer. Ann Oncol 27:2275–2283

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

I thank Sean Rudd for helpful input. The laboratory is mainly funded by Knut and Alice Wallenberg Foundation, the Swedish Research Council, the European Research Council, Swedish Cancer Society, the Swedish Children’s Cancer Foundation, the Strategic Research Foundation, the Swedish Pain Relief Foundation, AFA foundation, and the Torsten and Ragnar Söderberg Foundation.

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Authors and Affiliations

  1. Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    Thomas Helleday

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  1. Thomas Helleday
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Correspondence to Thomas Helleday .

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Editors and Affiliations

  1. Vertex Pharmaceuticals (Europe) Ltd, Abingdon, Oxfordshire, United Kingdom

    John Pollard

  2. Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom

    Nicola Curtin

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Helleday, T. (2018). Targeting DNA Repair in Anti-Cancer Treatments. In: Pollard, J., Curtin, N. (eds) Targeting the DNA Damage Response for Anti-Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-75836-7_1

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  • DOI: https://doi.org/10.1007/978-3-319-75836-7_1

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