DNA Repair Proteins as Therapeutic Targets in Ovarian Cancer

Author(s): César López-Camarillo*, Dolores G. Rincón, Erika Ruiz-García, Horacio Astudillo-de la Vega, Laurence A. Marchat.

Journal Name: Current Protein & Peptide Science

Volume 20 , Issue 4 , 2019

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Graphical Abstract:


Epithelial ovarian cancer is a serious public health problem worldwide with the highest mortality rate of all gynecologic cancers. The current standard-of-care for the treatment of ovarian cancer is based on chemotherapy based on adjuvant cisplatin/carboplatin and taxane regimens that represent the first-line agents for patients with advanced disease. The DNA repair activity of cancer cells determines the efficacy of anticancer drugs. These features make DNA repair mechanisms a promising target for novel cancer treatments. In this context a better understanding of the DNA damage response caused by antitumor agents has provided the basis for the use of DNA repair inhibitors to improve the therapeutic use of DNA-damaging drugs. In this review, we will discuss the functions of DNA repair proteins and the advances in targeting DNA repair pathways with special emphasis in the inhibition of HRR and BER in ovarian cancer. We focused in the actual efforts in the development and clinical use of poly (ADPribose) polymerase (PARP) inhibitors for the intervention of BRCA1/BRCA2-deficient ovarian tumors. The clinical development of PARP inhibitors in ovarian cancer patients with germline BRCA1/2 mutations and sporadic high-grade serous ovarian cancer is ongoing. Some phase II and phase III trials have been completed with promising results for ovarian cancer patients.

Keywords: Ovarian cancer, DNA repair, homologous recombination repair, base excision repair, poly (ADP-ribose) polymerase (PARP) inhibitors.

Jemal, A.; Siegel, R.; Xu, J.; Ward, E. Cancer statistics, 2010. CA Cancer J. Clin., 2010, 60, 277-300.
Rojas, V.; Hirshfield, K.M.; Ganesan, S.; Rodriguez-Rodriguez, L. Molecular characterization of epithelial ovarian cancer: Implications for diagnosis and treatment. Int. J. Mol. Sci., 2016, 17(12), E2113.
Vaughan, S.; Coward, J.I.; Bast, R.C., Jr; Berchuck, A.; Berek, J.S.; Brenton, J.D.; Coukos, G.; Crum, C.C.; Drapkin, R.; Etemadmoghadam, D.; Friedlander, M.; Gabra, H.; Kaye, S.B.; Lord, C.J.; Lengyel, E.; Levine, D.A.; McNeish, I.A.; Menon, U.; Mills, G.B.; Nephew, K.P.; Oza, A.M.; Sood, A.K. Stronach. E.A.; Walczak, H.; Bowtell, D.D.; Balkwill, F.R. Rethinking ovarian cancer: Recommendations for improving outcomes. Nat. Rev. Cancer, 2011, 11, 719-725.
Greenlee, R.T.; Hill-Harmon, M.B.; Murray, T.; Thun, M. Cancer statistics, 2001. CA Cancer J. Clin., 2001, 51, 15-36.
Sandercock, J.; Parmar, M.K.; Torri, V.; Qian, W. First-line treatment for advanced ovarian cancer: Paclitaxel, platinum and the evidence. Br. J. Cancer, 2002, 87, 815-824.
Ciccia, A.; Elledge, S.J. The DNA damage response: Making it safe to play with knives. Mol. Cell, 2010, 40, 179-204.
Wei, C.; Skopp, R.; Takata, M.; Takeda, S.; Price, C.M. Effects of double strand break repair proteins on vertebrate telomere structure. Nucleic Acids Res., 2002, 30, 2862-2870.
Helleday, T.; Petermann, E.; Lundin, C.; Hodgson, B.; Sharma, R.A. DNA repair pathways as targets for cancer therapy. Nat. Rev. Cancer, 2008, 8, 193-204.
Noll, D.M.; Mason, T.M.; Miller, P.S. Formation and repair of interstrand cross-links in DNA. Chem. Rev., 2006, 106(2), 277-301.
Alagoz, M.; Gilbert, D.C.; El-Khamisy, S.; Chalmers, A.J. DNA repair and resistance to topoisomerase I inhibitors: Mechanisms, biomarkers and therapeutic targets. Curr. Med. Chem., 2012, 19(23), 3874-3885.
Jeggo, P.A.; Geuting, V.; Löbrich, M. The role of homologous recombination in radiation-induced double-strand break repair. Radiother. Oncol., 2011, 101(1), 7-12.
Curtin, N. Therapeutic potential of drugs to modulate DNA repair in cancer. Expert Opin. Ther. Targets, 2007, 11, 783-799.
McHugh, P.J.; Spanswick, V.J.; Hartley, J.A. Repair of DNA interstrand crosslinks: Molecular mechanisms and clinical relevance. Lancet Oncol., 2001, 2, 483-490.
Lønning, P.E. Molecular basis for therapy resistance. Mol. Oncol., 2010, 4, 284-300.
Bartkova, J.; Horejsí, Z.; Koed, K.; Krämer, A.; Tort, F.; Zieger, K.; Guldberg, P.; Sehested, M.; Nesland, J.M.; Lukas, C.; Ørntoft, T.; Lukas, J.; Bartek, J. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature, 2005, 434(7035), 864-870.
Jian, D.; Ze-Hong, H.M.; Ling-Hua, H.M.; Mei-Yu, Y.G. Emerging cancer therapeutic opportunities target DNA-repair systems. Trends Pharmacol. Sci., 2006, 27, 338-344.
Sung, P.; Klein, H. Mechanism of homologous recombination: Mediators and helicases take on regulatory functions. Nat. Rev. Mol. Cell Biol., 2006, 10, 739-750.
Hoeijmakers, J.H. Genome maintenance mechanisms for preventing cancer. Nature, 2001, 411, 366-374.
Symington, L.S. Role of RAD52 epistasis group genes in homologous recombination and double-strand break repair. Microbiol. Mol. Biol. Rev., 2002, 66, 630-700.
Sigurdsson, S.; Van Komen, S.; Bussen, W.; Schild, D.; Albala, J.S.; Sung, P. Mediator function of the human Rad51B-Rad51 C complex in Rad51/RPA-catalyzed DNA strand exchange. Genes Dev., 2001, 15, 3308-3318.
Wong, A.K.C.; Pero, R.; Ormonde, P.A.; Tavtigian, S.V.; Bartel, P.L. RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene BRCA2. J. Biol. Chem., 1997, 272, 31941-31944.
Gabai-Kapara, E.; Lahad, A.; Kaufman, B.; Friedman, E.; Segev, S.; Renbaum, P.; Beeri, R.; Gal, M.; Grinshpun-Cohen, J.; Djemal, K.; Mandell, J.B.; Lee, M.K.; Beller, U.; Catane, R.; King, M.C. Levy-Lahad. E. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proc. Natl. Acad. Sci. USA, 2014, 111(39), 14205-14210.
Burma, S.; Chen, B.P.C.; Chen, D.J. Role of non-homologous end joining (NHEJ) in maintaining genomic integrity. DNA Repair (Amst.), 2006, 5, 1042-1048.
Yano, Y.; Yano, K.M.; Wang, S.Y.; Uematsu, N.; Lee, K.J.; Asaithamby, A.; Weterings, E.; Chen, D.J. Ku recruits XLF to DNA double-strand breaks. EMBO Rep., 2008, 9, 91-96.
Ochi, T.; Sibanda, B.L.; Wu, Q.; Chirgradz, D.Y. Bolanos-Barcia., V.M.; Blundell, T. Structural biology of DNA repair: Spatial organizational of the multi- component complexes of non-homologous end joining. J. Nucleic Acids, 2010, 2010, 621695.
Bennardo, N.; Cheng, A.; Huang, N.; Stark, J.M. Alternative-NHEJ is mechanistically distinct pathway of mammalian chromosome break repair. PLoS Genet., 2008, 4, e1000110-e1000120.
Iliakis, G. Backup pathways of NHEJ in cells of higher eukaryotes: Cell cycle dependence. Radiother. Oncol., 2009, 92, 310-315.
Neal, J.A.; Meek, K. Choosing the right path: Does DNA-PK help make the decision? Mutat. Res., 2011, 711, 73-86.
Friedman, J.I.; Stivers, J.T. Detection of damaged DNA bases by DNA glycosylase enzymes. Biochemistry, 2010, 49, 4957-4967.
Demple, B.; Sung, J.S. Molecular and biological roles of Ape1 protein in mammalian base excision repair. DNA Repair (Amst.), 2005, 4, 1442-1449.
Dogliotti, E.; Fortini, P.; Pascucci, B.; Parlanti, E. The mechanism of switching among multiple BER pathways. Prog. Nucleic Acid Res. Mol. Biol., 2001, 68, 3-27.
Curtin, N. Therapeutic potential of drugs to modulate DNA repair in cancer. Expert Opin. Ther. Targets, 2007, 11, 783-799.
Murai, J. Targeting DNA repair and replication stress in the treatment of ovarian cancer. Int. J. Clin. Oncol., 2017, 22(4), 619-628.
Zhu, Y.; Hu, J.; Hu, Y.; Liu, W. Targeting DNA repair pathways: A novel approach to reduce cancer therapeutic resistance. Cancer Treat. Rev., 2009, 35, 590-596.
Yoshida, K.; Miki, Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci., 2004, 95, 866-871.
Pellegrini, L.; Yu, D.S.; Lo, T.; Anand, S.; Lee, M.; Blundell, T.L.; Venkitaraman, A.R. Insights into DNA recombination from the structure of a RAD51-BRCA2 complex. Nature, 2002, 420, 287-293.
Ramus, S.J.; Harrington, P.; Pye, C.; DiCioccio, R.; Cox, M.; Garlinghouse-Jones, K.; Oakley-Girvan, I.; Jacobs, I.J.; Hardy, R.M.; Whittemore, A.; Ponder, B.A.; Piver, M.S.; Pharoah, P.D.; Gayther, S.A. The contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer. Hum. Mutat., 2007, 28, 1207-1215.
Turner, N.C.; Reis-Filho, J.S.; Russell, A.M.; Springall, R.J.; Ryder, K.; Steele, D.; Savage, K.; Gillett, C.E.; Schmitt, F.C.; Ashworth, A.; Tutt, A.N. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene, 2007, 26, 2126-2132.
Holstege, H.; Joosse, S.A.; Van Oostrom, C.T.; Nederlof, P.M.; de Vries, A.; Jonkers, J. High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer. Cancer Res., 2009, 69, 3625-3633.
Press, J.Z.; De Luca, A.; Boyd, N.; Young, S.; Troussard, A.; Ridge, Y.; Kaurah, P.; Kalloger, S.E.; Blood, K.A.; Smith, M.; Spellman, P.T.; Wang, Y.; Miller, D.M.; Horsman, D.; Faham, M.; Gilks, C.B.; Gray, J.; Huntsman, D.G. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer, 2008, 8, 17.
Schreiber, V.; Dantzer, F.; Ame, J.C.; De Murcia, G. Poly(ADP-ribose): Novel functions for an old molecule. Nat. Rev. Mol. Cell Biol., 2006, 7, 517-528.
Nguewa, P.A.; Fuertes, M.A.; Valladares, B.; Alonso, C.; Pérez, J.M. Poly(ADP-ribose) polymerases: Homology, structural domains and functions. Novel therapeutical applications. Prog. Biophys. Mol. Biol., 2005, 88, 143-172.
Bryant, H.E.; Schultz, N.; Thomas, H.D.; Parker, K.M.; Flower, D.; Lopez, E.; Kyle, S.; Meuth, M.; Curtin, N.J.; Helleday, T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature, 2005, 434, 913-917.
Farmer, H.; McCabe, N.; Lord, C.J.; Tutt, A.N.; Johnson, D.A.; Richardson, T.B.; Santarosa, M.; Dillon, K.J.; Hickson, I.; Knights, C.; Martin, N.M.; Jackson, S.P.; Smith, G.C.; Ashworth, A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature, 2005, 434, 917-921.
Fong, P.C.; Boss, D.S.; Yap, T.A.; Tutt, A.; Wu, P.; Mergui-Roelvink, M.; Mortimer, P.; Swaisland, H.; Lau, A.; O’Connor, M.J.; Ashworth, A.; Carmichael, J.; Kaye, S.B.; Schellens, J.H.; de Bono, J.S. Inhibition of poly(ADP-Ribose) polymerase in tumors from BRCA mutation Carriers. N. Engl. J. Med., 2009, 361, 123-134.
Fong, P.C.; Boss, D.S.; Carden, C.P.; Roelvink, M.; De Greve, J.; Gourley, C.M.; Carmichael, J.; De Bono, J.S.; Schellens, H.; Kaye, B. AZD2281 (KU-0059436), a PARP (poly ADP-ribose polymerase) inhibitor with single agent anticancer activity in patients with BRCA deficient ovarian cancer: Results from a phase I study J. Clin. Oncol, 2008, 26 (Suppl; abstr 5510).
Audeh, M.W.; Carmichael, J. Penson. R.T.; Friedlander, M.; Powell, B.; Bell-McGuinn, K.M.; Scott, C.; Weitzel, J.N.; Oaknin, A.; Loman, N.; Lu, K.; Schmutzler, R.K.; Matulonis, U.; Wickens, M.; Tutt, A. Oral poly(ADPribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: A proof-of-concept trial. Lancet, 2010, 376(9737), 245-251.
Gelmon, K.A.; Tischkowitz, M.; Mackay, H.; Swenerton, K.; Robidoux, A.; Tonkin, K.; Hirte, H.; Huntsman, D.; Clemons, M.; Gilks, B.; Yerushalmi, R.; Macpherson, E.; Carmichael, J.; Oza, A. 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., 2011, 12(9), 852-861.
Ledermann, J.A.; Harter, P.; Gourley, C.; Friedlander, M.; Vergote, I.; Rustin, G.; Scott, C.; Meier, W.; Shapira-Frommer, R.; Safra, T.; Matei, D.; Macpherson, E.; Watkins, C.; Carmichael, J.; Matulonis, U. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N. Engl. J. Med., 2012, 366(15), 1382-1392.
Evans, T.; Matulonis, U. PARP inhibitors in ovarian cancer: evidence, experience and clinical potential. Ther. Adv. Med. Oncol., 2017, 9(4), 253-267.
Lee, J.; Hays, J.; Annunziata, C.; Noonan, A.; Minasian, L.; Zujewski, J.; Yu, M.; Gordon, N.; Ji, J.; Sissung, T.M.; Figg, W.D.; Azad, N.; Wood, B.J.; Doroshow, J.; Kohn, E.C. Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. J. Natl. Cancer Inst., 2014, 106(6), dju089.
Oza, A.; Cibula, D.; Benzaquen, A.; Poole, C.; Mathijssen, R.; Sonke, G.; Colombo, N.; Špaček, J.; Vuylsteke, P.; Hirte, H.; Mahner, S.; Plante, M.; Schmalfeldt, B.; Mackay, H.; Rowbottom, J.; Lowe, E.S.; Dougherty, B.; Barrett, J.C.; Friedlander, M. Olaparib combined with chemotherapy for recurrent platinumsensitive ovarian cancer: a randomised phase 2 trial. Lancet Oncol., 2015, 16, 87-97.
Bell-McGuinn, K.; Brady, W.; Schilder, R.; Fracasso, P.; Moore, K.; Walker, J. A phase I study of continuous veliparib in combination with IV carboplatin/paclitaxel or IV/IP paclitaxel/cisplatin and bevacizumab in newly diagnosed patients with previously untreated epithelial ovarian, fallopian tube, or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study J. Clin. Oncol., 2015, 33 abstract 5507.
Matulonis, U.; Monk, B. PARP inhibitor and chemotherapy combination trials for the treatment of advanced malignancies: Does a development pathway forward exist? Ann. Oncol., 2017, 28, 443-447.
Liu, J.F.; Tolaney, S.M.; Birrer, M.; Fleming, G.F.; Buss, M.K.; Dahlberg, S.E.; Lee, H.; Whalen, C.; Tyburski, K.; Winer, E.; Ivy, P.; Matulonis, U.A. 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, 2013, 49(14), 2972-2978.
Liu, J.F.; Barry, W.T.; Birrer, M.; Lee, J.M.; Buckanovich, R.J.; Fleming, G.F.; Rimel, B.; Buss, M.K.; Nattam, S.; Hurteau, J.; Luo, W.; Quy, P.; Whalen, C.; Obermayer, L.; Lee, H.; Winer, E.P.; Kohn, E.C.; Ivy, S.P.; Matulonis, U.A. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: A randomized phase 2 study. Lancet Oncol., 2014, 15(11), 1207-1214.

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Article Details

Year: 2019
Page: [316 - 323]
Pages: 8
DOI: 10.2174/1389203719666180914091537
Price: $65

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