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Targeting DNA Repair

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Mechanisms of Drug Resistance in Cancer Therapy

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 249))

Abstract

Genomic instability is a characteristic of most human cancers and plays critical roles in both cancer development and progression. There are various forms of genomic instability arising from many different pathways, such as DNA damage from endogenous and exogenous sources, centrosome amplification, telomere damage, and epigenetic modifications. DNA-repair pathways can enable tumor cells to survive DNA damage. The failure to respond to DNA damage is a characteristic associated with genomic instability. Understanding of genomic instability in cancer is still very limited, but the further understanding of the molecular mechanisms through which the DNA damage response (DDR) operates, in combination with the elucidation of the genetic interactions between DDR pathways and other cell pathways, will provide therapeutic opportunities for the personalized medicine of cancer.

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References

  • Artandi SE, DePinho RA (2010) Telomeres and telomerase in cancer. Carcinogenesis 31:9–18

    Article  CAS  PubMed  Google Scholar 

  • Aubert G, Lansdorp PM (2008) Telomeres and aging. Physiol Rev 88:557–579

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Bartkova J, HoÅ™ejší Z, Koed K et al (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 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 

  • Bedikian AY, Papadopoulos NE, Kim KB et al (2009) A phase IB trial of intravenous INO-1001 plus oral temozolomide in subjects with unresectable stage-III or IV melanoma. Cancer Invest 27:756–763

    Article  CAS  PubMed  Google Scholar 

  • Bell O, Tiwari VK, Thoma NH, Schubeler D (2011) Determinants and dynamics of genome accessibility. Nat Rev Genet 12:554–564

    Article  CAS  PubMed  Google Scholar 

  • Blackburn EH (2000) Telomeres and telomerase. J Med 49:59–65

    CAS  Google Scholar 

  • Bouwman P, Aly A, Escandell JM et al (2010) 53BP1 loss rescues BRCA1 deficiency and is associated with triple negative and BRCA-mutated breast cancers. Nat Struct Mol Biol 17:688–695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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  CAS  PubMed  Google Scholar 

  • Bundred N, Gardovskis J, Jaskiewicz J et al (2013) Evaluation of the pharmacodynamics and pharmacokinetics of the PARP inhibitor olaparib: a phase I multicenter trial in patients scheduled for elective breast cancer surgery. Invest New Drugs 31:949–958

    Article  CAS  PubMed  Google Scholar 

  • Cedar H, Bergman Y (2009) Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet 10:295–304

    Article  CAS  PubMed  Google Scholar 

  • Ciccia A, Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40:179–204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • David SS, O’Shea VL, Kundu S (2007) Base-excision repair of oxidative DNA damage. Nature 447:941–950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Lange T (2010) How shelterin solves the telomere end-protection problem. Cold Spring Harb Symp Quant Biol 75:167–177

    Article  PubMed  Google Scholar 

  • Dean E, Middleton MR, Pwint T et al (2012) Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours. Br J Cancer 106:468–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Del Conte G, Sessa C, von Moos R et al (2014) Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours. Br J Cancer 111:651–659

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dent RA, Lindeman GJ, Clemons M et al (2013) Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer. Breast Cancer Res 15:R88

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Di Micco R, Fumagalli M, Cicalese A et al (2006) Oncogene-induced senescence is a DNA damage response triggered by DNA hyperreplication. Nature 444:638–642

    Article  PubMed  CAS  Google Scholar 

  • Doxsey S (2001) Re-evaluating centrosome function. Nat Rev Mol Cell Biol 2:688–698

    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 

  • Fackenthal JD, Olopade OI (2007) Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nat Rev Cancer 7:937–948

    Article  CAS  PubMed  Google Scholar 

  • Fang X, Zhang R (2011) Aneuploidy and tumourigenesis. Semin Cell Dev Biol 22:595–601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferguson LR, Chen H, Collins AR et al (2015) Genomic instability in human cancer: molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition. Semin Cancer Biol 35:S5–S24

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fishel R, Lescoe MK, Rao MRS, Copeland NG (1993) The human mutator gene homolog MSH2 and its association with hereditary non-polyposis colon cancer. Cell 75:1027–1038

    Article  CAS  PubMed  Google Scholar 

  • Fong PC, Yap TA, Boss DS et al (2009) Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol 28:2512–2519

    Article  CAS  Google Scholar 

  • Frizzell KM, Kraus WL (2009) PARP inhibitors and the treatment of breast cancer: beyond BRCA1/2? Breast Cancer Res 11:111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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  CAS  PubMed  Google Scholar 

  • Gergely F, Basto R (2008) Multiple centrosomes: together they stand, divided they fall. Genes Dev 22:2291–2296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glover DM, Leibowitz MH, McLean DA et al (1995) Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell 891:95–105

    Article  Google Scholar 

  • Gorgoulis VG, Vassiliou LVF, Karakaidos P et al (2005) Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434:907–913

    Article  CAS  PubMed  Google Scholar 

  • Greider CW (1991) Telomeres. Curr Opin Cell Biol 3:444–451

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Harley CB (1991) Telomere loss: mitotic clock or genetic time bomb. Mutat Res 256:271–282

    Article  CAS  PubMed  Google Scholar 

  • Harley CB, Sherwood SW (1997) Telomerase, checkpoints and cancer. Cancer Surv 29:263–284

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Hitchins MP (2010) Inheritance of epigenetic aberrations (constitutional epimutations) in cancer susceptibility. Adv Genet 70:201–243

    Article  CAS  PubMed  Google Scholar 

  • Hockemeyer D, Sfeir AJ, Shay JW et al (2005) POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end. EMBO J 24:2667–2678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoeijmakers JH (2009) DNA damage, aging, and cancer. N Engl J Med 361:1475–1485

    Article  CAS  PubMed  Google Scholar 

  • Isakoff SJ, Overmoyer B, Tung NM et al (2010) A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer. ASCO annual meeting abstracts. J Clin Oncol 28(15_suppl):1019

    Article  Google Scholar 

  • Jirincy J (2006) The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol 7:335–346

    Google Scholar 

  • Karlseder J, Hoke K, Mirzoeva OK et al (2004) The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response. PLoS Biol 2:E240

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Khodjakov A (2002) De novo formation of centrosomes in vertebrate cells arrested during S phase. J Cell Biol 158:1171–1181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ko MA, Rosario CO, Hudson JW et al (2005) Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis. Nat Genet 37:883–888

    Article  CAS  PubMed  Google Scholar 

  • Konishi A, de Lange T (2008) Cell cycle control of telomere protection and NHEJ revealed by a ts mutation in the DNA-binding domain of TRF2. Genes Dev 22:1221–1230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kummar S, Kinders R, Gutierrez ME et al (2009) Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol 27:2705–2711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwon M, Godinho SA, Chandhok NS et al (2008) Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. Genes Dev 22:2189–2203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leach FS, Nicolaides NC, Papadopoulos N, Liu B (1993) Mutations of a mutS homolog in hereditary non-polyposis colorectal cancer. Cell 75:1215–1225

    Article  CAS  PubMed  Google Scholar 

  • Lee JH, Jeong SY, Kim MJ et al (2015) MicroRNA-22 suppresses DNA repair and promotes genomic instability through targeting of MDC1. Cancer Res 75:1298

    Article  CAS  PubMed  Google Scholar 

  • Lengauer C, Kinzler KW, Vogelstein B (1997) Genetic instability in colorectal cancers. Nature 386:623–627

    Article  CAS  PubMed  Google Scholar 

  • Levy MZ, Allsopp RC, Futcher AB et al (1992) Telomere end-replication problem and cell aging. J Mol Biol 225:951–960

    Article  CAS  PubMed  Google Scholar 

  • Levy-Lahad E (2010) Fanconi anemia and breast cancer susceptibility meet again. Nat Genet 42:368–369

    Article  CAS  PubMed  Google Scholar 

  • Lieber MR (2010) NHEJ and its backup pathways in chromosomal translocations. Nat Struct Mol Biol 17:393–395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lindahl T, Barnes DE (2000) Repair of endogenous DNA damage. Cold Spring Harb Symp Quant Biol 65:127–133

    Article  CAS  PubMed  Google Scholar 

  • Liu JF, Tolaney SM, Birrer M et al (2013) A phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Eur J Cancer 49:2972–2978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loeb LA (1991) Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 51:3075–3079

    CAS  PubMed  Google Scholar 

  • Lord CJ, Ashworth A (2012) The DNA damage response and cancer therapy. Nature 481:287

    Article  CAS  PubMed  Google Scholar 

  • Mailand N, Bekker-Jensen S, Faustrup H et al (2007) RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 131:887–900

    Article  CAS  PubMed  Google Scholar 

  • Marthien V, Piel M, Basto RJ (2012) Never tear us apart – the importance of centrosome clustering. Cell Sci 125:3281–3292

    Article  CAS  Google Scholar 

  • Maxwell CA, Keats JJ, Belch AR et al (2005) Receptor forhyaluronan-mediated motility correlates with centrosome abnormalities in multiple myeloma and maintains mitotic integrity. Cancer Res 56:850–860

    Google Scholar 

  • McCabe N, Turner NC, Lord CJ et al (2006) Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res 66:8109–8115

    Article  CAS  PubMed  Google Scholar 

  • Miquel C, Jacob S, Grandjouan S et al (2007) Frequent alteration of DNA damage signalling and repair pathways in human colorectal cancers with microsatellite instability. Oncogene 26:5919–5926

    Article  CAS  PubMed  Google Scholar 

  • Moynahan ME, Jasin M (2010) Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol 11:196–207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Negrini S, Gorgoulis VG, Halazonetis TD (2010) Genomic instability – an evolving hallmark of cancer. Nat Rev Mol Cell Biol 11:220–228

    Article  CAS  PubMed  Google Scholar 

  • Nigg EA (2002) Centrosome aberrations: cause or consequence of cancer progression. Nat Rev Cancer 2:815–825

    Article  CAS  PubMed  Google Scholar 

  • Nigg EA, Stearns T (2011) The centrosome cycle: centriole biogenesis, duplication and inherent asymmetries. Nat Cell Biol 13:1154–1160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194:23–28

    Article  CAS  PubMed  Google Scholar 

  • O’Shaughnessy J, Osborne C, Pippen JE et al (2011) Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 364:205–214

    Article  PubMed  Google Scholar 

  • Ogden A, Rida PC, Aneja R (2012) Let’s huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy. Cell Death Differ 19:1255–1267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Papoutsis AJ, Borg JL, Selmin OI, Romagnolo DF (2012) BRCA-1 promoter hypermethylation and silencing induced by the aromatic hydrocarbon receptor-ligand TCDD are prevented by resveratrol in MCF-7 cells. J Nutr Biochem 23:1324–1332

    Article  CAS  PubMed  Google Scholar 

  • Penning TD, Zhu GD, Gandhi VB et al (2009) Discovery of the poly(ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-Yl]-1h-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer. J Med Chem 52:514–523

    Article  CAS  PubMed  Google Scholar 

  • Plummer R, Jones C, Middleton M et al (2008) Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res 14:7917–7923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plummer R, Lorigan P, Steven N et al (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 

  • Plummer R, Stephens P, Aissat-Daudigny L et al (2014) Phase 1 dose escalation study of the PARP inhibitor CEP-9722 as monotherapy or in combination with temozolomide in patients with solid tumors. Cancer Chemother Pharmacol 74:257–265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rajagopalan H, Lengauer C (2004) Aneuploidy and cancer. Nature 432:338–341

    Article  CAS  PubMed  Google Scholar 

  • Rajan A, Carter CA, Kelly RJ et al (2012) A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors. Clin Cancer Res 18:2344–2351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rouleau M, Patel A, Hendzel MJ et al (2010) PARP inhibition: PARP1 and beyond. Nat Rev Cancer 10:293–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Samol J, Ranson M, Scott E et al (2012) Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study. Invest New Drugs 30:1493–1500

    Article  CAS  PubMed  Google Scholar 

  • Schreiber V, Dantzer F, Ame JC, de Murcia G (2006) Poly(ADPribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7:517–528

    Article  CAS  PubMed  Google Scholar 

  • Sharma S, Kelly TK, Jones PA (2010) Epigenetics in cancer. Carcinogenesis 31:27–36

    Article  CAS  PubMed  Google Scholar 

  • Sproul D, Gilbert N, Bickmore WA (2005) The role of chromatin structure in regulating the expression of clustered genes. Nat Rev Genet 6:775–781

    Article  CAS  PubMed  Google Scholar 

  • Swann PF, Waters TR, Moulton DC (1996) Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. Science 273:1109–1111

    Article  CAS  PubMed  Google Scholar 

  • Tutt A, Robson M, Garber JE et al (2010) Oral poly(ADP-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  CAS  PubMed  Google Scholar 

  • Vilar E, Bartnik CM, Stenzel SL et al (2011) MRE11 deficiency increases sensitivity to poly(ADP-ribose) polymerase inhibition in microsatellite unstable colorectal cancers. Cancer Res 71:2632–2642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Warmerdam DO, Kanaar R (2010) Dealing with DNA damage: relationships between checkpoint and repair pathways. Mutat Res 704:2–11

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto N, Nokihara H, Yamada Y et al (2012) A phase I, dosefinding and pharmacokinetic study of olaparib (AZD2281) in Japanese patients with advanced solid tumors. Cancer Sci 103:504–509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhai L, Li S, Li X et al (2015) The nuclear expression of poly (ADP-ribose) polymerase-1 (PARP1) in invasive primary breast tumors is associated with chemotherapy sensitivity. Pathol Res Pract 211:130–137

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Early Drug Development for Innovative Therapy Division, European Institute of Oncology, Via Ripamonti, 435 20141, Milan, Italy

    Giuseppe Curigliano

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  1. Giuseppe Curigliano
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Correspondence to Giuseppe Curigliano .

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Editors and Affiliations

  1. Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy

    Mario Mandalà

  2. Department of Oncology, INSERM Res Unit 932, Institut Curie, Paris Cedex 05, France

    Emanuela Romano

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Curigliano, G. (2017). Targeting DNA Repair. In: Mandalà, M., Romano, E. (eds) Mechanisms of Drug Resistance in Cancer Therapy. Handbook of Experimental Pharmacology, vol 249. Springer, Cham. https://doi.org/10.1007/164_2017_31

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