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22-06-2017 | PARP inhibitors | Article

Targeting DNA repair and replication stress in the treatment of ovarian cancer

Journal: International Journal of Clinical Oncology

Author: Junko Murai

Publisher: Springer Japan

Abstract

Approximately half of high-grade serous epithelial ovarian cancers incur alterations in genes of homologous recombination (BRCA1, BRCA2, RAD51C, Fanconi anemia genes), and the rest incur alterations in other DNA repair pathways at high frequencies. Such cancer-specific gene alterations can confer selective sensitivity to DNA damaging agents such as cisplatin and carboplatin, topotecan, etoposide, doxorubicin, and gemcitabine. Originally presumed to inhibit DNA repair, PARP inhibitors that have recently been approved by the FDA for the treatment of advanced ovarian cancer also act as DNA damaging agents by inducing PARP–DNA complexes. These DNA damaging agents induce different types of DNA lesions that require various DNA repair genes for the repair, but commonly induce replication fork slowing or stalling, also referred to as replication stress. Replication stress activates DNA repair checkpoint proteins (ATR, CHK1), which prevent further DNA damage. Hence, targeting DNA repair genes or DNA repair checkpoint genes augments the anti-tumor activity of DNA damaging agents. This review describes the rational basis for using DNA repair and DNA repair checkpoint inhibitors as single agents. The review also presents the strategies combining these inhibitors with DNA damaging agents for ovarian cancer therapy based on specific gene alterations.

Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi:10.1016/j.cell.2011.02.013 CrossRefPubMed

Vesela E, Chroma K, Turi Z et al (2017) Common chemical inductors of replication stress: focus on cell-based studies. Biomolecules. doi:10.3390/biom7010019 PubMedPubMedCentral

Pommier Y (2006) Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer 6(10):789–802CrossRefPubMed

Strumberg D, Pilon AA, Smith M et al (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(11):3977–3987CrossRefPubMedPubMedCentral

Kelland L (2007) The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 7(8):573–584. doi:10.1038/nrc2167 CrossRefPubMed

Dietlein F, Thelen L, Reinhardt HC (2014) Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches. Trends Genet 30(8):326–339. doi:10.1016/j.tig.2014.06.003 CrossRefPubMed

Reinhold WC, Varma S, Sousa F et al (2014) NCI-60 whole exome sequencing and pharmacological Cell Miner analyses. PLoS One 9(7):e101670. doi:10.1371/journal.pone.0101670 CrossRefPubMedPubMedCentral

Varma S, Pommier Y, Sunshine M et al (2014) High resolution copy number variation data in the NCI-60 cancer cell lines from whole genome microarrays accessible through Cell Miner. PLoS One 9(3):e92047. doi:10.1371/journal.pone.0092047 CrossRefPubMedPubMedCentral

Reinhold WC, Sunshine M, Varma S et al (2015) Using cell miner 1.6 for systems pharmacology and genomic analysis of the NCI-60. Clin Cancer Res 21(17):3841–3852. doi:10.1158/1078-0432.CCR-15-0335 CrossRefPubMedPubMedCentral

10.

Sousa FG, Matuo R, Tang SW et al (2015) Alterations of DNA repair genes in the NCI-60 cell lines and their predictive value for anticancer drug activity. DNA Repair (Amst) 28:107–115. doi:10.1016/j.dnarep.2015.01.011 CrossRef

11.

Reinhold WC, Varma S, Sunshine M et al (2017) The NCI-60 methylome and its integration into CellMiner. Cancer Res 77(3):601–612. doi:10.1158/0008-5472.CAN-16-0655 CrossRefPubMed

12.

Konstantinopoulos PA, Ceccaldi R, Shapiro GI et al (2015) Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov 5(11):1137–1154. doi:10.1158/2159-8290.CD-15-0714 CrossRefPubMedPubMedCentral

13.

Cancer Genome Atlas Research N (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474(7353):609–615. doi:10.1038/nature10166 CrossRef

14.

Bajrami I, Frankum JR, Konde A et al (2014) Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity. Cancer Res 74(1):287–297. doi:10.1158/0008-5472.CAN-13-2541 CrossRefPubMed

15.

Kennedy RD, D’Andrea AD (2006) DNA repair pathways in clinical practice: lessons from pediatric cancer susceptibility syndromes. J Clin Oncol 24(23):3799–3808. doi:10.1200/JCO.2005.05.4171 CrossRefPubMed

16.

Burrell RA, Swanton C (2014) Tumour heterogeneity and the evolution of polyclonal drug resistance. Mol Oncol 8(6):1095–1111. doi:10.1016/j.molonc.2014.06.005 CrossRefPubMed

17.

Shigetomi H, Higashiura Y, Kajihara H et al (2012) Targeted molecular therapies for ovarian cancer: an update and future perspectives (review). Oncol Rep 28(2):395–408. doi:10.3892/or.2012.1833 PubMed

18.

Kelley MR, Logsdon D, Fishel ML (2014) Targeting DNA repair pathways for cancer treatment: what’s new? Future Oncol 10(7):1215–1237. doi:10.2217/fon.14.60 CrossRefPubMedPubMedCentral

19.

Stover EH, Konstantinopoulos PA, Matulonis UA et al (2016) Biomarkers of response and resistance to DNA repair targeted therapies. Clin Cancer Res 22(23):5651–5660. doi:10.1158/1078-0432.CCR-16-0247 CrossRefPubMed

20.

Brown JS, O’Carrigan B, Jackson SP et al (2017) Targeting DNA repair in cancer: beyond PARP inhibitors. Cancer Discov 7(1):20–37. doi:10.1158/2159-8290.CD-16-0860 CrossRefPubMed

21.

McLornan DP, List A, Mufti GJ (2014) Applying synthetic lethality for the selective targeting of cancer. N Engl J Med 371(18):1725–1735. doi:10.1056/NEJMra1407390 CrossRefPubMed

22.

Bryant HE, Schultz N, Thomas HD et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434(7035):913–917. doi:10.1038/nature03443 CrossRefPubMed

23.

Farmer H, McCabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035):917–921. doi:10.1038/nature03445 CrossRefPubMed

24.

Davidson D, Amrein L, Panasci L et al (2013) Small molecules, inhibitors of DNA-PK, targeting DNA repair, and beyond. Front Pharmacol 4:5. doi:10.3389/fphar.2013.00005 CrossRefPubMedPubMedCentral

25.

Willmore E, de Caux S, Sunter NJ et al (2004) A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia. Blood 103(12):4659–4665. doi:10.1182/blood-2003-07-2527 CrossRefPubMed

26.

Lin AB, McNeely SC, Beckmann RP (2017) Achieving precision death with cell cycle inhibitors that target DNA replication and repair. Clin Cancer Res. doi:10.1158/1078-0432.CCR-16-0083

27.

Srivas R, Shen JP, Yang CC et al (2016) A network of conserved synthetic lethal interactions for exploration of precision cancer therapy. Mol Cell 63(3):514–525. doi:10.1016/j.molcel.2016.06.022 CrossRefPubMed

28.

Mohni KN, Kavanaugh GM, Cortez D (2014) ATR pathway inhibition is synthetically lethal in cancer cells with ERCC1 deficiency. Cancer Res 74(10):2835–2845. doi:10.1158/0008-5472.CAN-13-3229 CrossRefPubMedPubMedCentral

29.

Maede Y, Shimizu H, Fukushima T et al (2014) Differential and common DNA repair pathways for topoisomerase I- and II-targeted drugs in a genetic DT40 repair cell screen panel. Mol Cancer Ther 13(1):214–220. doi:10.1158/1535-7163.MCT-13-0551 CrossRefPubMed

30.

Murai J, Huang SY, Das BB et al (2012) Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res 72(21):5588–5599. doi:10.1158/0008-5472.CAN-12-2753 CrossRefPubMedPubMedCentral

31.

Bruno PM, Liu Y, Park GY et al (2017) A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress. Nat Med 23(4):461–471. doi:10.1038/nm.4291 CrossRefPubMed

32.

Joshi PM, Sutor SL, Huntoon CJ et al (2014) Ovarian cancer-associated mutations disable catalytic activity of CDK12, a kinase that promotes homologous recombination repair and resistance to cisplatin and poly(ADP-ribose) polymerase inhibitors. J Biol Chem 289(13):9247–9253. doi:10.1074/jbc.M114.551143 CrossRefPubMedPubMedCentral

33.

Dedes KJ, Wetterskog D, Mendes-Pereira AM et al (2010) PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med 2(53):5375. doi:10.1126/scitranslmed.3001538 CrossRef

34.

McEllin B, Camacho CV, Mukherjee B et al (2010) PTEN loss compromises homologous recombination repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase inhibitors. Cancer Res 70(13):5457–5464. doi:10.1158/0008-5472.CAN-09-4295 CrossRefPubMedPubMedCentral

35.

Chernikova SB, Game JC, Brown JM (2012) Inhibiting homologous recombination for cancer therapy. Cancer Biol Ther 13(2):61–68. doi:10.4161/cbt.13.2.18872 CrossRefPubMedPubMedCentral

36.

Nemec AA, Wallace SS, Sweasy JB (2010) Variant base excision repair proteins: contributors to genomic instability. Semin Cancer Biol 20(5):320–328. doi:10.1016/j.semcancer.2010.10.010 CrossRefPubMedPubMedCentral

37.

Fishel ML, He Y, Smith ML et al (2007) Manipulation of base excision repair to sensitize ovarian cancer cells to alkylating agent temozolomide. Clin Cancer Res 13(1):260–267. doi:10.1158/1078-0432.CCR-06-1920 CrossRefPubMed

38.

Allinson SL (2010) DNA end-processing enzyme polynucleotide kinase as a potential target in the treatment of cancer. Future Oncol 6(6):1031–1042. doi:10.2217/fon.10.40 CrossRefPubMed

39.

Jaiswal AS, Banerjee S, Panda H et al (2009) A novel inhibitor of DNA polymerase beta enhances the ability of temozolomide to impair the growth of colon cancer cells. Mol Cancer Res 7(12):1973–1983. doi:10.1158/1541-7786.MCR-09-0309 CrossRefPubMedPubMedCentral

40.

Tang JB, Svilar D, Trivedi RN et al (2011) N-methylpurine DNA glycosylase and DNA polymerase beta modulate BER inhibitor potentiation of glioma cells to temozolomide. Neuro Oncol 13(5):471–486. doi:10.1093/neuonc/nor011 CrossRefPubMedPubMedCentral

41.

Sultana R, McNeill DR, Abbotts R et al (2012) Synthetic lethal targeting of DNA double-strand break repair deficient cells by human apurinic/apyrimidinic endonuclease inhibitors. Int J Cancer 131(10):2433–2444. doi:10.1002/ijc.27512 CrossRefPubMedPubMedCentral

42.

Wang Y, Ghosh G, Hendrickson EA (2009) Ku86 represses lethal telomere deletion events in human somatic cells. Proc Natl Acad Sci USA 106(30):12430–12435. doi:10.1073/pnas.0903362106 CrossRefPubMedPubMedCentral

43.

Weterings E, Gallegos AC, Dominick LN et al (2016) A novel small molecule inhibitor of the DNA repair protein Ku70/80. DNA Repair (Amst) 43:98–106. doi:10.1016/j.dnarep.2016.03.014 CrossRef

44.

Murai J, Zhang Y, Morris J et al (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(3):408–416. doi:10.1124/jpet.113.210146 CrossRefPubMedPubMedCentral

45.

Dungl DA, Maginn EN, Stronach EA (2015) Preventing damage limitation: targeting DNA-PKcs and DNA double-strand break repair pathways for ovarian cancer therapy. Front Oncol 5:240. doi:10.3389/fonc.2015.00240 CrossRefPubMedPubMedCentral

46.

McFadden MJ, Lee WK, Brennan JD et al (2014) Delineation of key XRCC4/Ligase IV interfaces for targeted disruption of non-homologous end joining DNA repair. Proteins 82(2):187–194. doi:10.1002/prot.24349 CrossRefPubMed

47.

Srivastava M, Nambiar M, Sharma S et al (2012) An inhibitor of nonhomologous end-joining abrogates double-strand break repair and impedes cancer progression. Cell 151(7):1474–1487. doi:10.1016/j.cell.2012.11.054 CrossRefPubMed

48.

Greco GE, Matsumoto Y, Brooks RC et al (2016) SCR7 is neither a selective nor a potent inhibitor of human DNA ligase IV. DNA Repair (Amst) 43:18–23. doi:10.1016/j.dnarep.2016.04.004 CrossRef

49.

Moldovan GL, D’Andrea AD (2009) How the fanconi anemia pathway guards the genome. Annu Rev Genet 43:223–249. doi:10.1146/annurev-genet-102108-134222 CrossRefPubMedPubMedCentral

50.

Arora S, Heyza J, Zhang H et al (2016) Identification of small molecule inhibitors of ERCC1-XPF that inhibit DNA repair and potentiate cisplatin efficacy in cancer cells. Oncotarget 7(46):75104–75117. doi:10.18632/oncotarget.12072 PubMedPubMedCentral

51.

Gentile F, Tuszynski JA, Barakat KH (2016) New design of nucleotide excision repair (NER) inhibitors for combination cancer therapy. J Mol Graph Model 65:71–82. doi:10.1016/j.jmgm.2016.02.010 CrossRefPubMed

52.

Fadda E (2013) Conformational determinants for the recruitment of ERCC1 by XPA in the nucleotide excision repair (NER) Pathway: structure and dynamics of the XPA binding motif. Biophys J 104(11):2503–2511. doi:10.1016/j.bpj.2013.04.023 CrossRefPubMedPubMedCentral

53.

Voter AF, Manthei KA, Keck JL (2016) A high-throughput screening strategy to identify protein-protein interaction inhibitors that block the Fanconi Anemia DNA repair pathway. J Biomol Screen 21(6):626–633. doi:10.1177/1087057116635503 CrossRefPubMedPubMedCentral

54.

Das DS, Das A, Ray A et al (2017) Blockade of deubiquitylating enzyme USP1 inhibits DNA repair and triggers apoptosis in multiple myeloma cells. Clin Cancer Res. doi:10.1158/1078-0432.CCR-16-2692

55.

Inoue A, Kikuchi S, Hishiki A et al (2014) A small molecule inhibitor of monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA) inhibits repair of interstrand DNA cross-link, enhances DNA double strand break, and sensitizes cancer cells to cisplatin. J Biol Chem 289(10):7109–7120. doi:10.1074/jbc.M113.520429 CrossRefPubMedPubMedCentral

56.

Actis ML, Ambaye ND, Evison BJ et al (2016) Identification of the first small-molecule inhibitor of the REV7 DNA repair protein interaction. Bioorg Med Chem 24(18):4339–4346. doi:10.1016/j.bmc.2016.07.026 CrossRefPubMed

57.

Zeng Z, Sharma A, Ju L et al (2012) TDP2 promotes repair of topoisomerase I-mediated DNA damage in the absence of TDP1. Nucleic Acids Res 40(17):8371–8380. doi:10.1093/nar/gks622 CrossRefPubMedPubMedCentral

58.

Pommier Y, Huang SY, Gao R et al (2014) Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2). DNA Repair (Amst) 19:114–129. doi:10.1016/j.dnarep.2014.03.020 CrossRef

59.

Murai J, Huang SY, Das BB et al (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(16):12848–12857. doi:10.1074/jbc.M111.333963 CrossRefPubMedPubMedCentral

60.

Huang SN, Pommier Y, Marchand C (2011) Tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibitors. Expert Opin Ther Pat 21(9):1285–1292. doi:10.1517/13543776.2011.604314 CrossRefPubMedPubMedCentral

61.

Marchand C, Abdelmalak M, Kankanala J et al (2016) Deazaflavin inhibitors of tyrosyl-DNA phosphodiesterase 2 (TDP2) specific for the human enzyme and active against cellular TDP2. ACS Chem Biol 11(7):1925–1933. doi:10.1021/acschembio.5b01047 CrossRefPubMed

62.

Das BB, Huang SY, Murai J et al (2014) PARP1-TDP1 coupling for the repair of topoisomerase I-induced DNA damage. Nucleic Acids Res 42(7):4435–4449. doi:10.1093/nar/gku088 CrossRefPubMedPubMedCentral

63.

Murai J, Marchand C, Shahane SA et al (2014) Identification of novel PARP inhibitors using a cell-based TDP1 inhibitory assay in a quantitative high-throughput screening platform. DNA Repair (Amst) 21:177–182. doi:10.1016/j.dnarep.2014.03.006 CrossRef

64.

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

65.

Hassa PO, Hottiger MO (2008) The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases. Front Biosci 13:3046–3082CrossRefPubMed

66.

Krishnakumar R, Kraus WL (2010) The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. Mol Cell 39(1):8–24. doi:10.1016/j.molcel.2010.06.017 CrossRefPubMedPubMedCentral

67.

Rouleau M, Patel A, Hendzel MJ et al (2010) PARP inhibition: PARP1 and beyond. Nat Rev Cancer 10(4):293–301. doi:10.1038/nrc2812 CrossRefPubMedPubMedCentral

68.

Juarez-Salinas H, Sims JL, Jacobson MK (1979) Poly(ADP-ribose) levels in carcinogen-treated cells. Nature 282(5740):740–741CrossRefPubMed

69.

Benjamin RC, Gill DM (1980) ADP-ribosylation in mammalian cell ghosts. Dependence of poly(ADP-ribose) synthesis on strand breakage in DNA. J Biol Chem 255(21):10493–10501PubMed

70.

Durkacz BW, Omidiji O, Gray DA et al (1980) (ADP-ribose)n participates in DNA excision repair. Nature 283(5747):593–596CrossRefPubMed

71.

Masson M, Niedergang C, Schreiber V et al (1998) XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage. Mol Cell Biol 18(6):3563–3571CrossRefPubMedPubMedCentral

72.

El-Khamisy SF, Masutani M, Suzuki H et al (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(19):5526–5533CrossRefPubMedPubMedCentral

73.

Shen Y, Rehman FL, Feng Y et al (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(18):5003–5015. doi:10.1158/1078-0432.CCR-13-1391 CrossRefPubMed

74.

Murai J, Huang SY, Renaud A et al (2014) Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther 13(2):433–443. doi:10.1158/1535-7163.MCT-13-0803 CrossRefPubMed

75.

Murai J, Pommier Y (2015) Classification of PARP inhibitors based on PARP trapping and catalytic inhibition, and rationale for combinations with topoisomerase I inhibitors and alkylating agents. Cancer Drug Discov D 83:261–274. doi:10.1007/978-3-319-14151-0_10 CrossRef

76.

Pommier Y, O'Connor MJ, de Bono J (2016) Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action. Sci Transl Med 8(362):362. doi:10.1126/scitranslmed.aaf9246 CrossRef

77.

Murai J, Feng Y, Yu GK et al (2016) Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition. Oncotarget 7(47):76534–76550. doi:10.18632/oncotarget.12266 PubMedPubMedCentral

78.

O’Sullivan CC, Moon DH, Kohn EC et al (2014) Beyond breast and ovarian cancers: PARP inhibitors for BRCA mutation-associated and BRCA-like solid tumors. Front Oncol 4:42. doi:10.3389/fonc.2014.00042 PubMedPubMedCentral

79.

Helleday T (2016) PARP inhibitor receives FDA breakthrough therapy designation in castration resistant prostate cancer: beyond germline BRCA mutations. Ann Oncol 27(5):755–757. doi:10.1093/annonc/mdw048 CrossRefPubMed

80.

Zeman MK, Cimprich KA (2014) Causes and consequences of replication stress. Nat Cell Biol 16(1):2–9. doi:10.1038/ncb2897 CrossRefPubMedPubMedCentral

81.

Cimprich KA, Cortez D (2008) ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 9(8):616–627. doi:10.1038/nrm2450 CrossRefPubMedPubMedCentral

82.

Yekezare M, Gomez-Gonzalez B, Diffley JF (2013) Controlling DNA replication origins in response to DNA damage − inhibit globally, activate locally. J Cell Sci 126(Pt 6):1297–1306. doi:10.1242/jcs.096701 CrossRefPubMed

83.

Mechali M (2010) Eukaryotic DNA replication origins: many choices for appropriate answers. Nat Rev Mol Cell Biol 11(10):728–738. doi:10.1038/nrm2976 CrossRefPubMed

84.

Branzei D, Foiani M (2008) Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol 9(4):297–308. doi:10.1038/nrm2351 CrossRefPubMed

85.

Feijoo C, Hall-Jackson C, Wu R et al (2001) Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing. J Cell Biol 154(5):913–923. doi:10.1083/jcb.200104099 CrossRefPubMedPubMedCentral

86.

King C, Diaz HB, McNeely S et al (2015) LY2606368 causes replication catastrophe and antitumor effects through CHK1-dependent mechanisms. Mol Cancer Ther 14(9):2004–2013. doi:10.1158/1535-7163.MCT-14-1037 CrossRefPubMed

87.

King C, Diaz H, Barnard D et al (2014) Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor. Invest New Drugs 32(2):213–226. doi:10.1007/s10637-013-0036-7 CrossRefPubMed

88.

Josse R, Martin SE, Guha R et al (2014) The ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase I inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res 74(23):6968–6979. doi:10.1158/0008-5472.CAN-13-3369 CrossRefPubMedPubMedCentral

89.

Seiler JA, Conti C, Syed A et al (2007) The intra-S-phase checkpoint affects both DNA replication initiation and elongation: single-cell and-DNA fiber analyses. Mol Cell Biol 27(16):5806–5818CrossRefPubMedPubMedCentral

90.

Toledo LI, Altmeyer M, Rask MB et al (2013) ATR prohibits replication catastrophe by preventing global exhaustion of RPA. Cell 155(5):1088–1103. doi:10.1016/j.cell.2013.10.043 CrossRefPubMed

91.

Berti M, Vindigni A (2016) Replication stress: getting back on track. Nat Struct Mol Biol 23(2):103–109. doi:10.1038/nsmb.3163 CrossRefPubMedPubMedCentral

92.

Syljuasen RG, Sorensen CS, Hansen LT et al (2005) Inhibition of human Chk1 causes increased initiation of DNA replication, phosphorylation of ATR targets, and DNA breakage. Mol Cell Biol 25(9):3553–3562. doi:10.1128/MCB.25.9.3553-3562.2005 CrossRefPubMedPubMedCentral

93.

Beck H, Nahse-Kumpf V, Larsen MS et al (2012) Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption. Mol Cell Biol 32(20):4226–4236. doi:10.1128/MCB.00412-12 CrossRefPubMedPubMedCentral

94.

Puigvert JC, Sanjiv K, Helleday T (2016) Targeting DNA repair, DNA metabolism and replication stress as anti-cancer strategies. FEBS J 283(2):232–245. doi:10.1111/febs.13574 CrossRefPubMed

95.

Sanjiv K, Hagenkort A, Calderon-Montano JM et al (2016) Cancer-specific synthetic lethality between ATR and CHK1 kinase activities. Cell Rep 17(12):3407–3416. doi:10.1016/j.celrep.2016.12.031 CrossRefPubMed

96.

McNeely S, Beckmann R, Bence Lin AK (2014) CHEK again: revisiting the development of CHK1 inhibitors for cancer therapy. Pharmacol Ther 142(1):1–10. doi:10.1016/j.pharmthera.2013.10.005 CrossRefPubMed

97.

Bowtell DD, Bohm S, Ahmed AA et al (2015) Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer 15(11):668–679. doi:10.1038/nrc4019 CrossRefPubMedPubMedCentral

98.

Lord CJ, Ashworth A (2016) BRCAness revisited. Nat Rev Cancer 16(2):110–120. doi:10.1038/nrc.2015.21 CrossRefPubMed

99.

Murai J, Pommier Y (2015) Classification of PARP inhibitors based on PAPR trapping and catalytic inhibition, and rationale for combination with topoisomerase I inhibitors and alkylating agents. In: Sharma NJCARA (ed) PARP inhibitors for cancer therapy, vol 83. Springer International Publishing, Switzerland. doi:10.1007/978-3-319-14151-0 CrossRef

Medicine Matters Oncology

Abstract