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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2022

Open Access 01-12-2022 | Review

The synthetic lethality of targeting cell cycle checkpoints and PARPs in cancer treatment

Authors: Shuangying Li, Liangliang Wang, Yuanyuan Wang, Changyi Zhang, Zhenya Hong, Zhiqiang Han

Published in: Journal of Hematology & Oncology | Issue 1/2022

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Abstract

Continuous cell division is a hallmark of cancer, and the underlying mechanism is tumor genomics instability. Cell cycle checkpoints are critical for enabling an orderly cell cycle and maintaining genome stability during cell division. Based on their distinct functions in cell cycle control, cell cycle checkpoints are classified into two groups: DNA damage checkpoints and DNA replication stress checkpoints. The DNA damage checkpoints (ATM-CHK2-p53) primarily monitor genetic errors and arrest cell cycle progression to facilitate DNA repair. Unfortunately, genes involved in DNA damage checkpoints are frequently mutated in human malignancies. In contrast, genes associated with DNA replication stress checkpoints (ATR-CHK1-WEE1) are rarely mutated in tumors, and cancer cells are highly dependent on these genes to prevent replication catastrophe and secure genome integrity. At present, poly (ADP-ribose) polymerase inhibitors (PARPi) operate through “synthetic lethality” mechanism with mutant DNA repair pathways genes in cancer cells. However, an increasing number of patients are acquiring PARP inhibitor resistance after prolonged treatment. Recent work suggests that a combination therapy of targeting cell cycle checkpoints and PARPs act synergistically to increase the number of DNA errors, compromise the DNA repair machinery, and disrupt the cell cycle, thereby increasing the death rate of cancer cells with DNA repair deficiency or PARP inhibitor resistance. We highlight a combinational strategy involving PARP inhibitors and inhibition of two major cell cycle checkpoint pathways, ATM-CHK2-TP53 and ATR-CHK1-WEE1. The biological functions, resistance mechanisms against PARP inhibitors, advances in preclinical research, and clinical trials are also reviewed.
Literature
1.
2.
Lindahl T, Barnes DE. Repair of endogenous DNA damage. Cold Spring Harb Symp Quant Biol. 2000;65:127–33.PubMedCrossRef
3.
Somyajit K, Gupta R, Sedlackova H, Neelsen KJ, Ochs F, Rask M-B, et al. Redox-sensitive alteration of replisome architecture safeguards genome integrity. Science. 2017;358(6364):797–802.PubMedCrossRef
4.
5.
6.
7.
McNevin CS, Cadoo K, Baird A-M, Murchan P, Sheils O, McDermott R, et al. Pathogenic variants as biomarkers for risk in prostate cancer. Cancers (Basel). 2021;13(22):5697.CrossRef
8.
9.
Gibson BA, Kraus WL. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol. 2012;13(7):411–24.PubMedCrossRef
10.
Padella A, Ghelli Luserna Di Rorà A, Marconi G, Ghetti M, Martinelli G, Simonetti G. Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies. J Hematol Oncol. 2022;15(1):10.PubMedPubMedCentralCrossRef
11.
Lin X, Jiang W, Rudolph J, Lee BJ, Luger K, Zha S. PARP inhibitors trap PARP2 and alter the mode of recruitment of PARP2 at DNA damage sites. Nucleic Acids Res. 2022;50(7):3958–73.PubMedPubMedCentralCrossRef
12.
13.
Kim D-S, Camacho CV, Kraus WL. Alternate therapeutic pathways for PARP inhibitors and potential mechanisms of resistance. Exp Mol Med. 2021;53(1):42–51.PubMedPubMedCentralCrossRef
14.
Fisher AEO, Hochegger H, Takeda S, Caldecott KW. Poly(ADP-ribose) polymerase 1 accelerates single-strand break repair in concert with poly(ADP-ribose) glycohydrolase. Mol Cell Biol. 2007;27(15):5597–605.PubMedPubMedCentralCrossRef
15.
Matthews HK, Bertoli C, de Bruin RAM. Cell cycle control in cancer. Nat Rev Mol Cell Biol. 2022;23(1):74–88.PubMedCrossRef
16.
17.
18.
Mirza MR, Coleman RL, González-Martín A, Moore KN, Colombo N, Ray-Coquard I, et al. The forefront of ovarian cancer therapy: update on PARP inhibitors. Ann Oncol. 2020;31(9):1148–59.PubMedCrossRef
19.
Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2(1): a001008.PubMedPubMedCentralCrossRef
20.
21.
Blackford AN, Jackson SP. ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol Cell. 2017;66(6):801–17.PubMedCrossRef
22.
Todo T, Kim ST, Hitomi K, Otoshi E, Inui T, Morioka H, et al. Flavin adenine dinucleotide as a chromophore of the Xenopus (6–4)photolyase. Nucleic Acids Res. 1997;25(4):764–8.PubMedPubMedCentralCrossRef
23.
Wienholz F, Vermeulen W, Marteijn JA. Amplification of unscheduled DNA synthesis signal enables fluorescence-based single cell quantification of transcription-coupled nucleotide excision repair. Nucleic Acids Res. 2017;45(9): e68.PubMedPubMedCentral
24.
Klein AV, Hambley TW. Platinum drug distribution in cancer cells and tumors. Chem Rev. 2009;109(10):4911–20.PubMedCrossRef
25.
Panagopoulos A, Altmeyer M. The hammer and the dance of cell cycle control. Trends Biochem Sci. 2021;46(4):301–14.PubMedCrossRef
26.
Aye Y, Li M, Long MJC, Weiss RS. Ribonucleotide reductase and cancer: biological mechanisms and targeted therapies. Oncogene. 2015;34(16):2011–21.PubMedCrossRef
27.
Barlow JH, Faryabi RB, Callén E, Wong N, Malhowski A, Chen HT, Gutierrez-Cruz G, Sun HW, McKinnon P, Wright G, Casellas R. A novel class of early replicating fragile sites that contribute to genome instability in B cell lymphomas. Cell. 2013;152(3):620.PubMedPubMedCentralCrossRef
28.
Tubbs A, Sridharan S, van Wietmarschen N, Maman Y, Callen E, Stanlie A, et al. Dual roles of poly(dA:dT) tracts in replication initiation and fork collapse. Cell. 2018;174(5):1127.PubMedPubMedCentralCrossRef
29.
30.
Varshney D, Spiegel J, Zyner K, Tannahill D, Balasubramanian S. The regulation and functions of DNA and RNA G-quadruplexes. Nat Rev Mol Cell Biol. 2020;21(8):459–74.PubMedPubMedCentralCrossRef
31.
García-Muse T, Aguilera A. Transcription-replication conflicts: how they occur and how they are resolved. Nat Rev Mol Cell Biol. 2016;17(9):553–63.PubMedCrossRef
32.
Hamperl S, Bocek MJ, Saldivar JC, Swigut T, Cimprich KA. Transcription-replication conflict orientation modulates R-loop levels and activates distinct DNA damage responses. Cell. 2017;170(4):774.PubMedPubMedCentralCrossRef
33.
Matos DA, Zhang J-M, Ouyang J, Nguyen HD, Genois M-M, Zou L. ATR protects the genome against R loops through a MUS81-triggered feedback loop. Mol Cell. 2020;77(3):514.PubMedCrossRef
34.
Kim S, Kang N, Park SH, Wells J, Hwang T, Ryu E, et al. ATAD5 restricts R-loop formation through PCNA unloading and RNA helicase maintenance at the replication fork. Nucleic Acids Res. 2020;48(13):7218–38.PubMedPubMedCentral
35.
Periyasamy M, Patel H, Lai C-F, Nguyen VTM, Nevedomskaya E, Harrod A, et al. APOBEC3B-mediated cytidine deamination is required for estrogen receptor action in breast cancer. Cell Rep. 2015;13(1):108–21.PubMedPubMedCentralCrossRef
36.
Yélamos J, Schreiber V, Dantzer F. Toward specific functions of poly(ADP-ribose) polymerase-2. Trends Mol Med. 2008;14(4):169–78.PubMedCrossRef
37.
Sukhanova MV, Hamon L, Kutuzov MM, Joshi V, Abrakhi S, Dobra I, et al. A single-molecule atomic force microscopy study of PARP1 and PARP2 recognition of base excision repair DNA intermediates. J Mol Biol. 2019;431(15):2655–73.PubMedCrossRef
38.
Fouquin A, Guirouilh-Barbat J, Lopez B, Hall J, Amor-Guéret M, Pennaneach V. PARP2 controls double-strand break repair pathway choice by limiting 53BP1 accumulation at DNA damage sites and promoting end-resection. Nucleic Acids Res. 2017;45(21):12325–39.PubMedPubMedCentralCrossRef
39.
40.
Riccio AA, Cingolani G, Pascal JM. PARP-2 domain requirements for DNA damage-dependent activation and localization to sites of DNA damage. Nucleic Acids Res. 2016;44(4):1691–702.PubMedCrossRef
41.
42.
43.
Caldecott KW. DNA single-strand break repair and human genetic disease. Trends Cell Biol. 2022;32(9):733–45.PubMedCrossRef
44.
Kim D-S, Challa S, Jones A, Kraus WL. PARPs and ADP-ribosylation in RNA biology: from RNA expression and processing to protein translation and proteostasis. Genes Dev. 2020;34(5–6):302–20.PubMedPubMedCentralCrossRef
45.
Reynolds P, Cooper S, Lomax M, O’Neill P. Disruption of PARP1 function inhibits base excision repair of a sub-set of DNA lesions. Nucleic Acids Res. 2015;43(8):4028–38.PubMedPubMedCentralCrossRef
46.
Marintchev A, Robertson A, Dimitriadis EK, Prasad R, Wilson SH, Mullen GP. Domain specific interaction in the XRCC1-DNA polymerase beta complex. Nucleic Acids Res. 2000;28(10):2049–59.PubMedPubMedCentralCrossRef
47.
Ali R, Alabdullah M, Alblihy A, Miligy I, Mesquita KA, Chan SY, et al. PARP1 blockade is synthetically lethal in XRCC1 deficient sporadic epithelial ovarian cancers. Cancer Lett. 2020;469:124–33.PubMedCrossRef
48.
Hanzlikova H, Kalasova I, Demin AA, Pennicott LE, Cihlarova Z, Caldecott KW. The importance of poly(ADP-Ribose) polymerase as a sensor of unligated okazaki fragments during DNA replication. Mol Cell. 2018;71(2):319.PubMedPubMedCentralCrossRef
49.
Marteijn JA, Lans H, Vermeulen W, Hoeijmakers JHJ. Understanding nucleotide excision repair and its roles in cancer and ageing. Nat Rev Mol Cell Biol. 2014;15(7):465–81.PubMedCrossRef
50.
Rocha CRR, Silva MM, Quinet A, Cabral-Neto JB, Menck CFM. DNA repair pathways and cisplatin resistance: an intimate relationship. Clinics (Sao Paulo). 2018;73(suppl 1):e478s.CrossRef
51.
Luijsterburg MS, Lindh M, Acs K, Vrouwe MG, Pines A, van Attikum H, et al. DDB2 promotes chromatin decondensation at UV-induced DNA damage. J Cell Biol. 2012;197(2):267–81.PubMedPubMedCentralCrossRef
52.
Sonoda Y, Sasaki Y, Gunji A, Shirai H, Araki T, Imamichi S, et al. Reduced tumorigenicity of mouse ES cells and the augmented anti-tumor therapeutic effects under deficiency. Cancers (Basel). 2020;12(4):1056.CrossRef
53.
Lord CJ, Tutt ANJ, Ashworth A. Synthetic lethality and cancer therapy: lessons learned from the development of PARP inhibitors. Annu Rev Med. 2015;66:455–70.PubMedCrossRef
54.
55.
Saleh-Gohari N, Bryant HE, Schultz N, Parker KM, Cassel TN, Helleday T. Spontaneous homologous recombination is induced by collapsed replication forks that are caused by endogenous DNA single-strand breaks. Mol Cell Biol. 2005;25(16):7158–69.PubMedPubMedCentralCrossRef
56.
Haince J-F, Kozlov S, Dawson VL, Dawson TM, Hendzel MJ, Lavin MF, et al. Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents. J Biol Chem. 2007;282(22):16441–53.PubMedCrossRef
57.
Haince J-F, McDonald D, Rodrigue A, Déry U, Masson J-Y, Hendzel MJ, et al. PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites. J Biol Chem. 2008;283(2):1197–208.PubMedCrossRef
58.
Schwertman P, Bekker-Jensen S, Mailand N. Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers. Nat Rev Mol Cell Biol. 2016;17(6):379–94.PubMedCrossRef
59.
Morgan WF, Cleaver JE. 3-Aminobenzamide synergistically increases sister-chromatid exchanges in cells exposed to methyl methanesulfonate but not to ultraviolet light. Mutat Res. 1982;104(6):361–6.PubMedCrossRef
60.
Kamp JA, Lemmens BBLG, Romeijn RJ, Changoer SC, van Schendel R, Tijsterman M. Helicase Q promotes homology-driven DNA double-strand break repair and prevents tandem duplications. Nat Commun. 2021;12(1):7126.PubMedPubMedCentralCrossRef
61.
Ahrabi S, Sarkar S, Pfister SX, Pirovano G, Higgins GS, Porter ACG, et al. A role for human homologous recombination factors in suppressing microhomology-mediated end joining. Nucleic Acids Res. 2016;44(12):5743–57.PubMedPubMedCentralCrossRef
62.
Wang M, Wu W, Wu W, Rosidi B, Zhang L, Wang H, et al. PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic Acids Res. 2006;34(21):6170–82.PubMedPubMedCentralCrossRef
63.
64.
Truong LN, Li Y, Shi LZ, Hwang PY-H, He J, Wang H, et al. Microhomology-mediated end joining and homologous recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells. Proc Natl Acad Sci U S A. 2013;110(19):7720–5.PubMedPubMedCentralCrossRef
65.
Errico A, Costanzo V. Mechanisms of replication fork protection: a safeguard for genome stability. Crit Rev Biochem Mol Biol. 2012;47(3):222–35.PubMedCrossRef
66.
67.
Neelsen KJ, Lopes M. Replication fork reversal in eukaryotes: from dead end to dynamic response. Nat Rev Mol Cell Biol. 2015;16(4):207–20.PubMedCrossRef
68.
Ronson GE, Piberger AL, Higgs MR, Olsen AL, Stewart GS, McHugh PJ, et al. PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation. Nat Commun. 2018;9(1):746.PubMedPubMedCentralCrossRef
69.
Berti M, Ray Chaudhuri A, Thangavel S, Gomathinayagam S, Kenig S, Vujanovic M, et al. Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nat Struct Mol Biol. 2013;20(3):347–54.PubMedPubMedCentralCrossRef
70.
71.
Kim D-S, Camacho CV, Nagari A, Malladi VS, Challa S, Kraus WL. Activation of PARP-1 by snoRNAs controls ribosome biogenesis and cell growth via the RNA helicase DDX21. Mol Cell. 2019;75(6):1270.PubMedPubMedCentralCrossRef
72.
Huang D, Kim D-S, Kraus WL. Specific binding of snoRNAs to PARP-1 promotes NAD-dependent catalytic activation. Biochemistry. 2020;59(16):1559–64.PubMedCrossRef
73.
Karakashev S, Zhu H, Yokoyama Y, Zhao B, Fatkhutdinov N, Kossenkov AV, et al. BET bromodomain inhibition synergizes with PARP inhibitor in epithelial ovarian cancer. Cell Rep. 2017;21(12):3398–405.PubMedPubMedCentralCrossRef
74.
Sobczak M, Pitt AR, Spickett CM, Robaszkiewicz A. PARP1 co-regulates EP300-BRG1-dependent transcription of genes involved in breast cancer cell proliferation and DNA repair. Cancers (Basel). 2019;11(10):1539.CrossRef
75.
Faraoni I, Consalvo MI, Aloisio F, Fabiani E, Giansanti M, Di Cristino F, et al. Cytotoxicity and differentiating effect of the poly(ADP-ribose) polymerase inhibitor olaparib in myelodysplastic syndromes. Cancers (Basel). 2019;11(9):1373.CrossRef
76.
Stakyte K, Rotheneder M, Lammens K, Bartho JD, Grädler U, Fuchß T, et al. Molecular basis of human ATM kinase inhibition. Nat Struct Mol Biol. 2021;28(10):789–98.PubMedCrossRef
77.
78.
Lee J-H, Paull TT. Cellular functions of the protein kinase ATM and their relevance to human disease. Nat Rev Mol Cell Biol. 2021;22(12):796–814.PubMedCrossRef
79.
Stolarova L, Kleiblova P, Janatova M, Soukupova J, Zemankova P, Macurek L, et al. Germline variants in cancer predisposition: stalemate rather than checkmate. Cells. 2020;9(12):2675.PubMedCentralCrossRef
80.
Álvarez-Quilón A, Serrano-Benítez A, Lieberman JA, Quintero C, Sánchez-Gutiérrez D, Escudero LM, et al. ATM specifically mediates repair of double-strand breaks with blocked DNA ends. Nat Commun. 2014;5:3347.PubMedCrossRef
81.
82.
Macheret M, Halazonetis TD. DNA replication stress as a hallmark of cancer. Annu Rev Pathol. 2015;10:425–48.PubMedCrossRef
83.
Grandori C, Gomez-Roman N, Felton-Edkins ZA, Ngouenet C, Galloway DA, Eisenman RN, et al. c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I. Nat Cell Biol. 2005;7(3):311–8.PubMedCrossRef
84.
Jones RM, Mortusewicz O, Afzal I, Lorvellec M, García P, Helleday T, et al. Increased replication initiation and conflicts with transcription underlie cyclin E-induced replication stress. Oncogene. 2013;32(32):3744–53.PubMedCrossRef
85.
Kotsantis P, Silva LM, Irmscher S, Jones RM, Folkes L, Gromak N, et al. Increased global transcription activity as a mechanism of replication stress in cancer. Nat Commun. 2016;7:13087.PubMedPubMedCentralCrossRef
86.
Zou L, Elledge SJ. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science. 2003;300(5625):1542–8.PubMedCrossRef
87.
88.
89.
90.
Byun TS, Pacek M, Yee M-C, Walter JC, Cimprich KA. Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev. 2005;19(9):1040–52.PubMedPubMedCentralCrossRef
91.
92.
93.
Roos WP, Kaina B. DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett. 2013;332(2):237–48.PubMedCrossRef
94.
de Klein A, Muijtjens M, van Os R, Verhoeven Y, Smit B, Carr AM, et al. Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice. Curr Biol. 2000;10(8):479–82.PubMedCrossRef
95.
Bradbury A, Hall S, Curtin N, Drew Y. Targeting ATR as cancer therapy: A new era for synthetic lethality and synergistic combinations? Pharmacol Ther. 2020;207: 107450.PubMedCrossRef
96.
Nie Y, Lang T. The interaction between ATRIP and MCM complex is essential for ATRIP chromatin loading and its phosphorylation in mantle cell lymphoma cells. Pharmazie. 2017;72(11):670–3.PubMed
97.
Buisson R, Boisvert JL, Benes CH, Zou L. Distinct but concerted roles of ATR, DNA-PK, and Chk1 in countering replication stress during S phase. Mol Cell. 2015;59(6):1011–24.PubMedPubMedCentralCrossRef
98.
Visconti R, Della Monica R, Grieco D. Cell cycle checkpoint in cancer: a therapeutically targetable double-edged sword. J Exp Clin Cancer Res. 2016;35(1):153.PubMedPubMedCentralCrossRef
99.
Narayanaswamy PB, Tkachuk S, Haller H, Dumler I, Kiyan Y. CHK1 and RAD51 activation after DNA damage is regulated via urokinase receptor/TLR4 signaling. Cell Death Dis. 2016;7(9): e2383.PubMedPubMedCentralCrossRef
100.
Sørensen CS, Syljuåsen RG. Safeguarding genome integrity: the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication. Nucleic Acids Res. 2012;40(2):477–86.PubMedCrossRef
101.
Wu X, Shell SM, Liu Y, Zou Y. ATR-dependent checkpoint modulates XPA nuclear import in response to UV irradiation. Oncogene. 2007;26(5):757–64.PubMedCrossRef
102.
Dart DA, Adams KE, Akerman I, Lakin ND. Recruitment of the cell cycle checkpoint kinase ATR to chromatin during S-phase. J Biol Chem. 2004;279(16):16433–40.PubMedCrossRef
103.
104.
Sørensen CS, Hansen LT, Dziegielewski J, Syljuåsen RG, Lundin C, Bartek J, et al. The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair. Nat Cell Biol. 2005;7(2):195–201.PubMedCrossRef
105.
Parmar K, Kochupurakkal BS, Lazaro J-B, Wang ZC, Palakurthi S, Kirschmeier PT, et al. The CHK1 inhibitor prexasertib exhibits monotherapy activity in high-grade serous ovarian cancer models and sensitizes to PARP inhibition. Clin Cancer Res. 2019;25(20):6127–40.PubMedPubMedCentralCrossRef
106.
Kabeche L, Nguyen HD, Buisson R, Zou L. A mitosis-specific and R loop-driven ATR pathway promotes faithful chromosome segregation. Science. 2018;359(6371):108–14.PubMedCrossRef
107.
Couch FB, Bansbach CE, Driscoll R, Luzwick JW, Glick GG, Bétous R, et al. ATR phosphorylates SMARCAL1 to prevent replication fork collapse. Genes Dev. 2013;27(14):1610–23.PubMedPubMedCentralCrossRef
108.
109.
Bitler BG, Watson ZL, Wheeler LJ, Behbakht K. PARP inhibitors: clinical utility and possibilities of overcoming resistance. Gynecol Oncol. 2017;147(3):695–704.PubMedPubMedCentralCrossRef
110.
Gupta R, Somyajit K, Narita T, Maskey E, Stanlie A, Kremer M, et al. DNA repair network analysis reveals shieldin as a key regulator of NHEJ and PARP inhibitor sensitivity. Cell. 2018;173(4):972.PubMedPubMedCentralCrossRef
111.
Lin KK, Harrell MI, Oza AM, Oaknin A, Ray-Coquard I, Tinker AV, et al. Reversion mutations in circulating tumor DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma. Cancer Discov. 2019;9(2):210–9.PubMedCrossRef
112.
AlHilli MM, Becker MA, Weroha SJ, Flatten KS, Hurley RM, Harrell MI, et al. In vivo anti-tumor activity of the PARP inhibitor niraparib in homologous recombination deficient and proficient ovarian carcinoma. Gynecol Oncol. 2016;143(2):379–88.PubMedPubMedCentralCrossRef
113.
Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature. 2008;451(7182):1116–20.PubMedPubMedCentralCrossRef
114.
Barber LJ, Sandhu S, Chen L, Campbell J, Kozarewa I, Fenwick K, et al. Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor. J Pathol. 2013;229(3):422–9.PubMedCrossRef
115.
Ter Brugge P, Kristel P, van der Burg E, Boon U, de Maaker M, Lips E, et al. Mechanisms of therapy resistance in patient-derived xenograft models of BRCA1-deficient breast cancer. J Natl Cancer Inst. 2016;108(11):djw148.CrossRef
116.
Price CM, Boltz KA, Chaiken MF, Stewart JA, Beilstein MA, Shippen DE. Evolution of CST function in telomere maintenance. Cell Cycle. 2010;9(16):3157–65.PubMedPubMedCentralCrossRef
117.
Zimmermann M, Lottersberger F, Buonomo SB, Sfeir A, de Lange T. 53BP1 regulates DSB repair using Rif1 to control 5’ end resection. Science. 2013;339(6120):700–4.PubMedPubMedCentralCrossRef
118.
Noordermeer SM, Adam S, Setiaputra D, Barazas M, Pettitt SJ, Ling AK, et al. The shieldin complex mediates 53BP1-dependent DNA repair. Nature. 2018;560(7716):117–21.PubMedPubMedCentralCrossRef
119.
Drost R, Dhillon KK, van der Gulden H, van der Heijden I, Brandsma I, Cruz C, et al. BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1. J Clin Invest. 2016;126(8):2903–18.PubMedPubMedCentralCrossRef
120.
Wang Y, Bernhardy AJ, Cruz C, Krais JJ, Nacson J, Nicolas E, et al. The BRCA1-Δ11q alternative splice isoform bypasses germline mutations and promotes therapeutic resistance to PARP inhibition and cisplatin. Cancer Res. 2016;76(9):2778–90.PubMedPubMedCentralCrossRef
121.
Zhou J, Gelot C, Pantelidou C, Li A, Yücel H, Davis RE, et al. A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors. Nat Cancer. 2021;2(6):598–610.PubMedPubMedCentralCrossRef
122.
Taglialatela A, Alvarez S, Leuzzi G, Sannino V, Ranjha L, Huang J-W, et al. Restoration of replication fork stability in BRCA1- and BRCA2-deficient cells by inactivation of SNF2-family fork remodelers. Mol Cell. 2017;68(2):414.PubMedPubMedCentralCrossRef
123.
Rondinelli B, Gogola E, Yücel H, Duarte AA, van de Ven M, van der Sluijs R, et al. EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation. Nat Cell Biol. 2017;19(11):1371–8.PubMedCrossRef
124.
Lemaçon D, Jackson J, Quinet A, Brickner JR, Li S, Yazinski S, et al. MRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells. Nat Commun. 2017;8(1):860.PubMedPubMedCentralCrossRef
125.
Schlacher K, Wu H, Jasin M. A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. Cancer Cell. 2012;22(1):106–16.PubMedPubMedCentralCrossRef
126.
Ray Chaudhuri A, Callen E, Ding X, Gogola E, Duarte AA, Lee J-E, et al. Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature. 2016;535(7612):382–7.PubMedCrossRef
127.
Krastev DB, Wicks AJ, Lord CJ. PARP inhibitors–trapped in a toxic love affair. Cancer Res. 2021;81(22):5605–7.PubMedCrossRef
128.
Zandarashvili L, Langelier M-F, Velagapudi UK, Hancock MA, Steffen JD, Billur R, et al. Structural basis for allosteric PARP-1 retention on DNA breaks. Science. 2020;368(6486):eaax6367.PubMedPubMedCentralCrossRef
129.
Murai J, Huang S-YN, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012;72(21):5588–99.PubMedPubMedCentralCrossRef
130.
Schoonen PM, Talens F, Stok C, Gogola E, Heijink AM, Bouwman P, et al. Progression through mitosis promotes PARP inhibitor-induced cytotoxicity in homologous recombination-deficient cancer cells. Nat Commun. 2017;8:15981.PubMedPubMedCentralCrossRef
131.
Pettitt SJ, Krastev DB, Brandsma I, Dréan A, Song F, Aleksandrov R, et al. Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. Nat Commun. 2018;9(1):1849.PubMedPubMedCentralCrossRef
132.
Gogola E, Duarte AA, de Ruiter JR, Wiegant WW, Schmid JA, de Bruijn R, et al. Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality. Cancer Cell. 2018;33(6):1078.PubMedCrossRef
133.
Moudry P, Watanabe K, Wolanin KM, Bartkova J, Wassing IE, Watanabe S, et al. TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity. J Cell Biol. 2016;212(3):281–8.PubMedPubMedCentralCrossRef
134.
Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A. 1987;84(21):7735–8.PubMedPubMedCentralCrossRef
135.
Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE, et al. Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics. 2011;21(3):152–61.PubMedPubMedCentralCrossRef
136.
Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE, Gottesman MM. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat Rev Cancer. 2018;18(7):452–64.PubMedPubMedCentralCrossRef
137.
Vaidyanathan A, Sawers L, Gannon A-L, Chakravarty P, Scott AL, Bray SE, et al. ABCB1 (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer cells. Br J Cancer. 2016;115(4):431–41.PubMedPubMedCentralCrossRef
138.
Chen Y, Hao Q, Wang S, Cao M, Huang Y, Weng X, et al. Inactivation of the tumor suppressor p53 by long noncoding RNA RMRP. Proc Natl Acad Sci U S A. 2021;118(29):e2026813118.
139.
140.
Patch A-M, Christie EL, Etemadmoghadam D, Garsed DW, George J, Fereday S, et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature. 2015;521(7553):489–94.PubMedCrossRef
141.
Briz O, Perez-Silva L, Al-Abdulla R, Abete L, Reviejo M, Romero MR, et al. What “The Cancer Genome Atlas” database tells us about the role of ATP-binding cassette (ABC) proteins in chemoresistance to anticancer drugs. Expert Opin Drug Metab Toxicol. 2019;15(7):577–93.PubMedCrossRef
142.
Bajrami I, Frankum JR, Konde A, Miller RE, Rehman FL, Brough R, et al. Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity. Cancer Res. 2014;74(1):287–97.PubMedCrossRef
143.
Karthikeyan S, Hoti SL. Development of fourth generation ABC inhibitors from natural products: a novel approach to overcome cancer multidrug resistance. Anticancer Agents Med Chem. 2015;15(5):605–15.PubMedCrossRef
144.
Moskwa P, Buffa FM, Pan Y, Panchakshari R, Gottipati P, Muschel RJ, et al. miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Mol Cell. 2011;41(2):210–20.PubMedCrossRef
145.
Choi YE, Meghani K, Brault M-E, Leclerc L, He YJ, Day TA, et al. Platinum and PARP inhibitor resistance due to overexpression of MicroRNA-622 in BRCA1-mutant ovarian cancer. Cell Rep. 2016;14(3):429–39.PubMedPubMedCentralCrossRef
146.
Meghani K, Fuchs W, Detappe A, Drané P, Gogola E, Rottenberg S, et al. Multifaceted impact of MicroRNA 493–5p on genome-stabilizing pathways induces platinum and PARP inhibitor resistance in BRCA2-mutated carcinomas. Cell Rep. 2018;23(1):100–11.PubMedPubMedCentralCrossRef
147.
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123–34.PubMedCrossRef
148.
Gralewska P, Gajek A, Marczak A, Mikuła M, Ostrowski J, Śliwińska A, et al. PARP inhibition increases the reliance on ATR/CHK1 checkpoint signaling leading to synthetic lethality-an alternative treatment strategy for epithelial ovarian cancer cells independent from HR effectiveness. Int J Mol Sci. 2020;21(24):9715.PubMedCentralCrossRef
149.
Yazinski SA, Comaills V, Buisson R, Genois M-M, Nguyen HD, Ho CK, et al. ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Genes Dev. 2017;31(3):318–32.PubMedPubMedCentralCrossRef
150.
Kim H, Xu H, George E, Hallberg D, Kumar S, Jagannathan V, et al. Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models. Nat Commun. 2020;11(1):3726.PubMedPubMedCentralCrossRef
151.
Dréan A, Williamson CT, Brough R, Brandsma I, Menon M, Konde A, et al. Modeling therapy resistance in -mutant cancers. Mol Cancer Ther. 2017;16(9):2022–34.PubMedPubMedCentralCrossRef
152.
Johnson N, Johnson SF, Yao W, Li Y-C, Choi Y-E, Bernhardy AJ, et al. Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance. Proc Natl Acad Sci U S A. 2013;110(42):17041–6.PubMedPubMedCentralCrossRef
153.
Weston VJ, Oldreive CE, Skowronska A, Oscier DG, Pratt G, Dyer MJS, et al. The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Blood. 2010;116(22):4578–87.PubMedCrossRef
154.
Lloyd RL, Wijnhoven PWG, Ramos-Montoya A, Wilson Z, Illuzzi G, Falenta K, et al. Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells. Oncogene. 2020;39(25):4869–83.PubMedPubMedCentralCrossRef
155.
Mak JPY, Ma HT, Poon RYC. Synergism between ATM and PARP1 inhibition involves DNA damage and abrogating the G DNA damage checkpoint. Mol Cancer Ther. 2020;19(1):123–34.PubMedCrossRef
156.
Jette NR, Radhamani S, Arthur G, Ye R, Goutam S, Bolyos A, et al. Combined poly-ADP ribose polymerase and ataxia-telangiectasia mutated/Rad3-related inhibition targets ataxia-telangiectasia mutated-deficient lung cancer cells. Br J Cancer. 2019;121(7):600–10.PubMedPubMedCentralCrossRef
157.
Wang C, Tang M, Chen Z, Nie L, Li S, Xiong Y, et al. Genetic vulnerabilities upon inhibition of DNA damage response. Nucleic Acids Res. 2021;49(14):8214–31.PubMedPubMedCentralCrossRef
158.
Huntoon CJ, Flatten KS, Wahner Hendrickson AE, Huehls AM, Sutor SL, Kaufmann SH, et al. ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy independent of BRCA status. Cancer Res. 2013;73(12):3683–91.PubMedPubMedCentralCrossRef
159.
Meng X, Bi J, Li Y, Yang S, Zhang Y, Li M, et al. AZD1775 increases sensitivity to olaparib and gemcitabine in cancer cells with p53 mutations. Cancers (Basel). 2018;10(5):149.CrossRef
160.
Peasland A, Wang LZ, Rowling E, Kyle S, Chen T, Hopkins A, et al. Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines. Br J Cancer. 2011;105(3):372–81.PubMedPubMedCentralCrossRef
161.
Ning J-F, Stanciu M, Humphrey MR, Gorham J, Wakimoto H, Nishihara R, et al. Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma. Nat Commun. 2019;10(1):2910.PubMedPubMedCentralCrossRef
162.
Neeb A, Herranz N, Arce-Gallego S, Miranda S, Buroni L, Yuan W, et al. Advanced prostate cancer with ATM loss: PARP and ATR inhibitors. Eur Urol. 2021;79(2):200–11.PubMedCrossRef
163.
Perkhofer L, Schmitt A, Romero Carrasco MC, Ihle M, Hampp S, Ruess DA, et al. ATM deficiency generating genomic instability sensitizes pancreatic ductal adenocarcinoma cells to therapy-induced DNA damage. Cancer Res. 2017;77(20):5576–90.PubMedCrossRef
164.
Lotan TL, Kaur HB, Salles DC, Murali S, Schaeffer EM, Lanchbury JS, et al. Homologous recombination deficiency (HRD) score in germline BRCA2- versus ATM-altered prostate cancer. Mod Pathol. 2021;34(6):1185–93.PubMedPubMedCentralCrossRef
165.
Gout J, Perkhofer L, Morawe M, Arnold F, Ihle M, Biber S, et al. Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer. Gut. 2021;70(4):743–60.PubMedCrossRef
166.
Farrés J, Martín-Caballero J, Martínez C, Lozano JJ, Llacuna L, Ampurdanés C, et al. Parp-2 is required to maintain hematopoiesis following sublethal γ-irradiation in mice. Blood. 2013;122(1):44–54.PubMedCrossRef
167.
Farrés J, Llacuna L, Martin-Caballero J, Martínez C, Lozano JJ, Ampurdanés C, et al. PARP-2 sustains erythropoiesis in mice by limiting replicative stress in erythroid progenitors. Cell Death Differ. 2015;22(7):1144–57.PubMedCrossRef
168.
Navarro J, Gozalbo-López B, Méndez AC, Dantzer F, Schreiber V, Martínez C, et al. PARP-1/PARP-2 double deficiency in mouse T cells results in faulty immune responses and T lymphomas. Sci Rep. 2017;7:41962.PubMedPubMedCentralCrossRef
169.
Galindo-Campos MA, Bedora-Faure M, Farrés J, Lescale C, Moreno-Lama L, Martínez C, et al. Coordinated signals from the DNA repair enzymes PARP-1 and PARP-2 promotes B-cell development and function. Cell Death Differ. 2019;26(12):2667–81.PubMedPubMedCentralCrossRef
170.
Illuzzi G, Staniszewska AD, Gill SJ, Pike A, McWilliams L, Critchlow SE, et al. Preclinical characterization of AZD5305, a next generation, highly selective PARP1 inhibitor and trapper. Clin Cancer Res. 2022.
171.
DiDomenico N. AZD5305 more tolerable than earlier PARP agents. Cancer Discov. 2022;12(7):1602.CrossRef
172.
Anderson VE, Walton MI, Eve PD, Boxall KJ, Antoni L, Caldwell JJ, et al. CCT241533 is a potent and selective inhibitor of CHK2 that potentiates the cytotoxicity of PARP inhibitors. Cancer Res. 2011;71(2):463–72.PubMedPubMedCentralCrossRef
173.
Xu Z, Vandenberg CJ, Lieschke E, Di Rago L, Scott CL, Majewski IJ. CHK2 inhibition provides a strategy to suppress hematologic toxicity from PARP inhibitors. Mol Cancer Res. 2021;19(8):1350–60.PubMedCrossRef
174.
Arienti KL, Brunmark A, Axe FU, McClure K, Lee A, Blevitt J, et al. Checkpoint kinase inhibitors: SAR and radioprotective properties of a series of 2-arylbenzimidazoles. J Med Chem. 2005;48(6):1873–85.PubMedCrossRef
175.
Höglund A, Strömvall K, Li Y, Forshell LP, Nilsson JA. Chk2 deficiency in Myc overexpressing lymphoma cells elicits a synergistic lethal response in combination with PARP inhibition. Cell Cycle. 2011;10(20):3598–607.PubMedPubMedCentralCrossRef
176.
Xiao G, Lundine D, Annor GK, Canar J, Ellison V, Polotskaia A, et al. Gain-of-function mutant p53 R273H interacts with replicating DNA and PARP1 in breast cancer. Cancer Res. 2020;80(3):394–405.PubMedCrossRef
177.
Liu Q, Gheorghiu L, Drumm M, Clayman R, Eidelman A, Wszolek MF, et al. PARP-1 inhibition with or without ionizing radiation confers reactive oxygen species-mediated cytotoxicity preferentially to cancer cells with mutant TP53. Oncogene. 2018;37(21):2793–805.PubMedPubMedCentralCrossRef
178.
Smeby J, Kryeziu K, Berg KCG, Eilertsen IA, Eide PW, Johannessen B, et al. Molecular correlates of sensitivity to PARP inhibition beyond homologous recombination deficiency in pre-clinical models of colorectal cancer point to wild-type TP53 activity. EBioMedicine. 2020;59: 102923.PubMedPubMedCentralCrossRef
179.
Sizemore ST, Mohammad R, Sizemore GM, Nowsheen S, Yu H, Ostrowski MC, et al. Synthetic lethality of PARP inhibition and ionizing radiation is p53-dependent. Mol Cancer Res. 2018;16(7):1092–102.PubMedPubMedCentralCrossRef
180.
Kim H, George E, Ragland R, Rafail S, Zhang R, Krepler C, et al. Targeting the ATR/CHK1 axis with PARP inhibition results in tumor regression in -mutant ovarian cancer models. Clin Cancer Res. 2017;23(12):3097–108.PubMedCrossRef
181.
Fang Y, McGrail DJ, Sun C, Labrie M, Chen X, Zhang D, et al. Sequential therapy with PARP and WEE1 inhibitors minimizes toxicity while maintaining efficacy. Cancer Cell. 2019;35(6):851.PubMedPubMedCentralCrossRef
182.
Brill E, Yokoyama T, Nair J, Yu M, Ahn Y-R, Lee J-M. Prexasertib, a cell cycle checkpoint kinases 1 and 2 inhibitor, increases toxicity of PARP inhibition by preventing Rad51 foci formation in wild type high-grade serous ovarian cancer. Oncotarget. 2017;8(67):111026–40.PubMedPubMedCentralCrossRef
183.
Smith HL, Prendergast L, Curtin NJ. Exploring the synergy between PARP and CHK1 inhibition in matched mutant and corrected cells. Cancers (Basel). 2020;12(4):878.CrossRef
184.
Lallo A, Frese KK, Morrow CJ, Sloane R, Gulati S, Schenk MW, et al. The combination of the PARP inhibitor olaparib and the WEE1 inhibitor AZD1775 as a new therapeutic option for small cell lung cancer. Clin Cancer Res. 2018;24(20):5153–64.PubMedCrossRef
185.
Lin X, Chen D, Zhang C, Zhang X, Li Z, Dong B, et al. Augmented antitumor activity by olaparib plus AZD1775 in gastric cancer through disrupting DNA damage repair pathways and DNA damage checkpoint. J Exp Clin Cancer Res. 2018;37(1):129.PubMedPubMedCentralCrossRef
186.
Parsels LA, Karnak D, Parsels JD, Zhang Q, Vélez-Padilla J, Reichert ZR, et al. PARP1 trapping and DNA replication stress enhance radiosensitization with combined WEE1 and PARP inhibitors. Mol Cancer Res. 2018;16(2):222–32.PubMedCrossRef
187.
Stopsack KH. Efficacy of PARP inhibition in metastatic castration-resistant prostate cancer is very different with non-BRCA DNA repair alterations: reconstructing prespecified endpoints for cohort B from the phase 3 PROfound trial of olaparib. Eur Urol. 2021;79(4):442–5.PubMedCrossRef
188.
Kwon DH, Booth CM, Prasad V. Untangling the PROfound trial for advanced prostate cancer: Is there really a role for olaparib? Eur Urol. 2021;79(6):710–2.PubMedCrossRef
189.
Abida W, Campbell D, Patnaik A, Shapiro JD, Sautois B, Vogelzang NJ, et al. Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: analysis from the phase II TRITON2 study. Clin Cancer Res. 2020;26(11):2487–96.PubMedPubMedCentralCrossRef
190.
de Bono JS, Mehra N, Scagliotti GV, Castro E, Dorff T, Stirling A, et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 2021;22(9):1250–64.PubMedCrossRef
191.
Tung NM, Robson ME, Ventz S, Santa-Maria CA, Nanda R, Marcom PK, et al. TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol. 2020;38(36):4274–82.PubMedCrossRef
192.
193.
Silk AW, Kaufman H, Gabrail N, Mehnert J, Zloza A. Abstract CT026: phase 1b study of intratumoral coxsackievirus A21 (CVA21) and systemic pembrolizumab in advanced melanoma patients: interim results of the CAPRA clinical trial. Cancer Res. 2017;77(13 Supplement):CT026.CrossRef
194.
Hamilton E, Falchook GS, Wang JS, Fu S, Li BT, editors. Abstract CT025: phase Ib study of adavosertib in combination with olaparib in patients with refractory solid tumors: dose escalation. In: Proceedings: AACR Annual Meeting 2019; Mar 29-Apr 3, 2019; Atlanta, GA; 2019.
195.
Madariaga A, Oza AM. Wee1 inhibition in recurrent serous uterine cancer: science paving the way in a challenging disease. J Clin Oncol. 2021;39(14):1513–7.PubMedCrossRef
196.
Hamilton EP, Wang JS-Z, Falchook G, Jones SF, Cook C, Mugundu G, et al. A phase Ib study of AZD1775 and olaparib combination in patients with refractory solid tumors. J Clin Oncol. 2016;34(15_suppl):5562.CrossRef
197.
Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl): Abstract nr 2609.
Metadata
Title
The synthetic lethality of targeting cell cycle checkpoints and PARPs in cancer treatment
Authors
Shuangying Li
Liangliang Wang
Yuanyuan Wang
Changyi Zhang
Zhenya Hong
Zhiqiang Han
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2022
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-022-01360-x

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