Targeting the DNA damage response in cancer

Abstract

DNA damage response (DDR) pathway is the coordinated cellular network dealing with the identification, signaling, and repair of DNA damage. It tightly regulates cell cycle progression and promotes DNA repair to minimize DNA damage to daughter cells. Key proteins involved in DDR are frequently mutated/inactivated in human cancers and promote genomic instability, a recognized hallmark of cancer. Besides being an intrinsic property of tumors, DDR also represents a unique therapeutic opportunity. Indeed, inhibition of DDR is expected to delay repair, causing persistent unrepaired breaks, to interfere with cell cycle progression, and to sensitize cancer cells to several DNA-damaging agents, such as radiotherapy and chemotherapy. In addition, DDR defects in cancer cells have been shown to render these cells more dependent on the remaining pathways, which could be targeted very specifically (synthetic lethal approach). Research over the past two decades has led to the synthesis and testing of hundreds of small inhibitors against key DDR proteins, some of which have shown antitumor activity in human cancers. In parallel, the search for synthetic lethality interaction is broadening the use of DDR inhibitors. In this review, we discuss the state-of-art of ataxia-telangiectasia mutated, ataxia-telangiectasia-and-Rad3-related protein, checkpoint kinase 1, Wee1 and Polθ inhibitors, highlighting the results obtained in the ongoing clinical trials both in monotherapy and in combination with chemotherapy and radiotherapy.

Keywords

ATM / ATR / Chk1 / DNA damage response / Polθ / solid tumors / Wee1

References

[1] ChapmanJR, TaylorMR, BoultonSJ. Playing the end game: DNA double-strand break repair pathway choice. Mol Cell. 2012; 47(4): 497-510.

[2] GroellyFJ, FawkesM, DaggRA, Blackford AN, TarsounasM. Targeting DNA damage response pathways in cancer. Nat Rev Cancer. 2023; 23(2): 78-94.

[3] JacksonSP, BartekJ. The DNA-damage response in human biology and disease. Nature. 2009; 461(7267): 1071-1078.

[4] HanahanD, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144(5): 646-674.

[5] TaylorAMR, Rothblum-Oviatt C, EllisNA, et al. Chromosome instability syndromes. Nat Rev Dis Primers. 2019; 5(1): 64.

[6] CarrassaL, DamiaG. DNA damage response inhibitors: mechanisms and potential applications in cancer therapy. Cancer Treat Rev. 2017; 60: 139-151.

[7] O’ConnorMJ. Targeting the DNA damage response in cancer. Mol Cell. 2015; 60(4): 547-560.

[8] LiQ, QianW, ZhangY, Hu L, ChenS, XiaY. A new wave of innovations within the DNA damage response. Signal Transduct Target Ther. 2023; 8(1): 338.

[9] MatsuokaS, BallifBA, SmogorzewskaA, et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 2007; 316(5828): 1160-1166.

[10] PriyaB, RaviS, KirubakaranS. Targeting ATM and ATR for cancer therapeutics: inhibitors in clinic. Drug Discov Today. 2023; 28(8): 103662.

[11] HoeijmakersJH. DNA damage, aging, and cancer. N Engl J Med. 2009; 361(15): 1475-1485.

[12] SmithHL, Southgate H, TweddleDA, CurtinNJ. DNA damage checkpoint kinases in cancer. Expert Rev Mol Med. 2020; 22: e2.

[13] VlatkovicT, Veldwijk MR, GiordanoFA, HerskindC. Targeting cell cycle checkpoint kinases to overcome intrinsic radioresistance in brain tumor cells. Cancers. 2022; 14(3): 701.

[14] LeeJH. Targeting the ATM pathway in cancer: opportunities, challenges and personalized therapeutic strategies. Cancer Treat Rev. 2024; 129: 102808.

[15] LavinMF, KozlovS, GateiM, Kijas AW. ATM-dependent phosphorylation of all three members of the MRN complex: from sensor to adaptor. Biomolecules. 2015; 5(4): 2877-2902.

[16] LeeJH, PaullTT. Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science. 2004; 304(5667): 93-96.

[17] YouZ, Chahwan C, BailisJ, HunterT, Russell P. ATM activation and its recruitment to damaged DNA require binding to the C terminus of Nbs1. Mol Cell Biol. 2005; 25(13): 5363-5379.

[18] McCarthy-LeoC, Darwiche F, TainskyMA. DNA repair mechanisms, protein interactions and therapeutic targeting of the MRN complex. Cancers. 2022; 14(21): 5278.

[19] WeberAM, RyanAJ. ATM and ATR as therapeutic targets in cancer. Pharmacol Ther. 2015; 149: 124-138.

[20] ShilohY, ZivY. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol. 2013; 14(4): 197-210.

[21] LeeJH, MandMR, DeshpandeRA, et al. Ataxia telangiectasia-mutated (ATM) kinase activity is regulated by ATP-driven conformational changes in the Mre11/Rad50/Nbs1 (MRN) complex. J Biol Chem. 2013; 288(18): 12840-12851.

[22] BartekJ, LukasJ. DNA damage checkpoints: from initiation to recovery or adaptation. Curr Opin Cell Biol. 2007; 19(2): 238-245.

[23] DeckbarD, JeggoPA, LobrichM. Understanding the limitations of radiation-induced cell cycle checkpoints. Crit Rev Biochem Mol Biol. 2011; 46(4): 271-283.

[24] ShibataA, JeggoPA. ATM’s role in the repair of DNA double-strand breaks. Genes. 2021; 12(9): 1370.

[25] ZanniniL, DeliaD, BuscemiG. CHK2 kinase in the DNA damage response and beyond. J Mol Cell Biol. 2014; 6(6): 442-457.

[26] YehYH, HuangYF, LinTY, Shieh SY. The cell cycle checkpoint kinase CHK2 mediates DNA damage-induced stabilization of TTK/hMps1. Oncogene. 2009; 28(10): 1366-1378.

[27] AdamsCJ, GrahamAL, JanssonM, et al. ATM and Chk2 kinase target the p53 cofactor Strap. EMBO Rep. 2008; 9(12): 1222-1229.

[28] BrunoT, De Nicola F, IezziS, et al. Che-1 phosphorylation by ATM/ATR and Chk2 kinases activates p53 transcription and the G2/M checkpoint. Cancer Cell. 2006; 10(6): 473-486.

[29] ChengQ, ChenJ. Mechanism of p53 stabilization by ATM after DNA damage. Cell Cycle. 2010; 9(3): 472-478.

[30] HiraoA, KongYY, MatsuokaS, et al. DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science. 2000; 287(5459): 1824-1827.

[31] KarakostisK, Malbert-Colas L, ThermouA, VojtesekB, Fahraeus R. The DNA damage sensor ATM kinase interacts with the p53 mRNA and guides the DNA damage response pathway. Mol Cancer. 2024; 23(1): 21.

[32] AbbasT, DuttaA. p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 2009; 9(6): 400-414.

[33] BiegingKT, MelloSS, AttardiLD. Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer. 2014; 14(5): 359-3570.

[34] WeberAM, Drobnitzky N, DeveryAM, et al. Phenotypic consequences of somatic mutations in the ataxia-telangiectasia mutated gene in non-small cell lung cancer. Oncotarget. 2016; 7(38): 60807-60822.

[35] PaullTT, Woolley PR. A-T neurodegeneration and DNA damage-induced transcriptional stress. DNA Repair. 2024; 135: 103647.

[36] GarciaMEG, KirschDG, ReitmanZJ. Targeting the ATM kinase to enhance the efficacy of radiotherapy and outcomes for cancer patients. Semin Radiat Oncol. 2022; 32(1): 3-14.

[37] KantidzeOL, Velichko AK, LuzhinAV, PetrovaNV, RazinSV. Synthetically lethal interactions of ATM, ATR, and DNA-PKcs. Trends Cancer. 2018; 4(11): 755-768.

[38] SaxenaS, ZouL. Hallmarks of DNA replication stress. Mol Cell. 2022; 82(12): 2298-2314.

[39] CimprichKA, CortezD. ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol. 2008; 9(8): 616-627.

[40] MarechalA, ZouL. DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol. 2013; 5(9): a012716.

[41] Unsal-KacmazK, SancarA. Quaternary structure of ATR and effects of ATRIP and replication protein A on its DNA binding and kinase activities. Mol Cell Biol. 2004; 24(3): 1292-1300.

[42] ZouL, Elledge SJ. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science. 2003; 300(5625): 1542-1548.

[43] VassinVM, Anantha RW, SokolovaE, KannerS, Borowiec JA. Human RPA phosphorylation by ATR stimulates DNA synthesis and prevents ssDNA accumulation during DNA-replication stress. J Cell Sci. 2009; 122: 4070-4080.

[44] WuCS, OuyangJ, MoriE, et al. SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway. Genes Dev. 2014; 28(13): 1472-1484.

[45] Navadgi-PatilVM, Burgers PM. A tale of two tails: activation of DNA damage checkpoint kinase Mec1/ATR by the 9-1-1 clamp and by Dpb11/TopBP1. DNA Repair. 2009; 8(9): 996-1003.

[46] OhashiE, Takeishi Y, UedaS, TsurimotoT. Interaction between Rad9-Hus1-Rad1 and TopBP1 activates ATR-ATRIP and promotes TopBP1 recruitment to sites of UV-damage. DNA Repair. 2014; 21: 1-11.

[47] BuissonR, NirajJ, RodrigueA, et al. Coupling of homologous recombination and the checkpoint by ATR. Mol Cell. 2017; 65(2): 336-346.

[48] LeeTH, ParkJM, LeemSH, Kang TH. Coordinated regulation of XPA stability by ATR and HERC2 during nucleotide excision repair. Oncogene. 2014; 33(1): 19-25.

[49] WangLC, Gautier J. The Fanconi anemia pathway and ICL repair: implications for cancer therapy. Crit Rev Biochem Mol Biol. 2010; 45(5): 424-439.

[50] LeungW, Simoneau A, SaxenaS, et al. ATR protects ongoing and newly assembled DNA replication forks through distinct mechanisms. Cell Rep. 2023; 42(7): 112792.

[51] YinY, LeeWTC, GuptaD, et al. A basal-level activity of ATR links replication fork surveillance and stress response. Mol Cell. 2021; 81(20): 4243-4257.

[52] EfeyanA, Serrano M. p53: guardian of the genome and policeman of the oncogenes. Cell Cycle. 2007; 6(9): 1006-1010.

[53] QiuZ, Oleinick NL, ZhangJ. ATR/CHK1 inhibitors and cancer therapy. Radiother Oncol. 2018; 126(3): 450-464.

[54] SorensenCS, Syljuasen RG, FalckJ, et al. Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A. Cancer Cell. 2003; 3(3): 247-258.

[55] PengCY, GravesPR, ThomaRS, Wu Z, ShawAS, Piwnica-WormsH. Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science. 1997; 277(5331): 1501-1505.

[56] GeenenJJJ, Schellens JHM. Molecular pathways: targeting the protein kinase Wee1 in cancer. Clin Cancer Res. 2017; 23(16): 4540-4544.

[57] MoiseevaTN, QianC, SugitaniN, Osmanbeyoglu HU, BakkenistCJ. WEE1 kinase inhibitor AZD1775 induces CDK1 kinase-dependent origin firing in unperturbed G1-and S-phase cells. Proc Natl Acad Sci U S A. 2019; 116(48): 23891-23893.

[58] FeijooC, Hall-Jackson C, WuR, et al. 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. 2001; 154(5): 913-923.

[59] SaldivarJC, CortezD, CimprichKA. The essential kinase ATR: ensuring faithful duplication of a challenging genome. Nat Rev Mol Cell Biol. 2017; 18(10): 622-636.

[60] SanjivK, Hagenkort A, Calderon-MontanoJM, et al. Cancer-specific synthetic lethality between ATR and CHK1 kinase activities. Cell Rep. 2016; 17(12): 3407-3416.

[61] KhetarpalP, DasS, PanigrahiI, Munshi A. Primordial dwarfism: overview of clinical and genetic aspects. Mol Genet Genomics. 2016; 291(1): 1-15.

[62] WaskiewiczE, Vasiliou M, Corcoles-SaezI, ChaRS. Cancer genome datamining and functional genetic analysis implicate mechanisms of ATM/ATR dysfunction underpinning carcinogenesis. Commun Biol. 2021; 4(1): 363.

[63] da CostaA, Chowdhury D, ShapiroGI, D’AndreaAD, Konstantinopoulos PA. Targeting replication stress in cancer therapy. Nat Rev Drug Discov. 2023; 22(1): 38-58.

[64] SmithJ, ThoLM, XuN, Gillespie DA. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res. 2010; 108: 73-112.

[65] ZauggK, SuYW, ReillyPT, et al. Cross-talk between Chk1 and Chk2 in double-mutant thymocytes. Proc Natl Acad Sci U S A. 2007; 104(10): 3805-3810.

[66] ChatterjeeN, WalkerGC. Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagen. 2017; 58(5): 235-263.

[67] KennedyRD, D’Andrea AD. DNA repair pathways in clinical practice: lessons from pediatric cancer susceptibility syndromes. J Clin Oncol. 2006; 24(23): 3799-3808.

[68] CaldecottKW. Causes and consequences of DNA single-strand breaks. Trends Biochem Sci. 2024; 49(1): 68-78.

[69] FishelR. Mismatch repair. J Biol Chem. 2015; 290(44): 26395-26403.

[70] KleinHL. Genome instabilities arising from ribonucleotides in DNA. DNA Repair. 2017; 56: 26-32.

[71] DianovGL, Hubscher U. Mammalian base excision repair: the forgotten archangel. Nucleic Acids Res. 2013; 41(6): 3483-3490.

[72] PolettoM, Legrand AJ, FletcherSC, DianovGL. p53 coordinates base excision repair to prevent genomic instability. Nucleic Acids Res. 2016; 44(7): 3165-3175.

[73] EnsmingerM, IloffL, EbelC, Nikolova T, KainaB, LöbrichM. DNA breaks and chromosomal aberrations arise when replication meets base excision repair. J Cell Biol. 2014; 206(1): 29-43.

[74] CaffreyPJ, Delaney S. Chromatin and other obstacles to base excision repair: potential roles in carcinogenesis. Mutagenesis. 2020; 35(1): 39-50.

[75] JacobsAL, ScharP. DNA glycosylases, in DNA repair and beyond. Chromosoma. 2012; 121(1): 1-20.

[76] BrooksSC, Adhikary S, RubinsonEH, EichmanBF. Recent advances in the structural mechanisms of DNA glycosylases. Biochim Biophys Acta. 2013; 1834(1): 247-271.

[77] MeasR, Smerdon MJ. Nucleosomes determine their own patch size in base excision repair. Sci Rep. 2016; 6: 27122.

[78] WeaverAN, YangES. Beyond DNA repair: additional functions of PARP-1 in cancer. Front Oncol. 2013; 3: 290.

[79] HowardMJ, Cavanaugh NA, BatraVK, ShockDD, BeardWA, WilsonSH. DNA polymerase beta nucleotide-stabilized template misalignment fidelity depends on local sequence context. J Biol Chem. 2020; 295(2): 529-538.

[80] MortusewiczO, Leonhardt H. XRCC1 and PCNA are loading platforms with distinct kinetic properties and different capacities to respond to multiple DNA lesions. BMC Mol Biol. 2007; 8: 81.

[81] BeardWA, HortonJK, PrasadR, Wilson SH. Eukaryotic base excision repair: new approaches shine light on mechanism. Annu Rev Biochem. 2019; 88: 137-162.

[82] MattarMM, ZekriAN, HusseinN, Morsy H, EsmatG, AminMA. Polymorphisms of base-excision repair genes and the hepatocarcinogenesis. Gene. 2018; 675: 62-68.

[83] PatronoC, Sterpone S, TestaA, CozziR. Polymorphisms in base excision repair genes: breast cancer risk and individual radiosensitivity. World J Clin Oncol. 2014; 5(5): 874-882.

[84] WallaceSS, MurphyDL, SweasyJB. Base excision repair and cancer. Cancer Lett. 2012; 327(1-2): 73-89.

[85] LordCJ, Ashworth A. PARP inhibitors: synthetic lethality in the clinic. Science. 2017; 355(6330): 1152-1158.

[86] Serrano-BenitezA, Wells SE, Drummond-ClarkeL, et al. Unrepaired base excision repair intermediates in template DNA strands trigger replication fork collapse and PARP inhibitor sensitivity. EMBO J. 2023; 42(18): e113190.

[87] MarteijnJA, LansH, VermeulenW, Hoeijmakers JH. Understanding nucleotide excision repair and its roles in cancer and ageing. Nat Rev Mol Cell Biol. 2014; 15(7): 465-481.

[88] KuperJ, KiskerC. At the core of nucleotide excision repair. Curr Opin Struct Biol. 2023; 80: 102605.

[89] KimJ, LiCL, ChenX, et al. Lesion recognition by XPC, TFIIH and XPA in DNA excision repair. Nature. 2023; 617(7959): 170-175.

[90] SugasawaK. Molecular mechanisms of DNA damage recognition for mammalian nucleotide excision repair. DNA Repair. 2016; 44: 110-117.

[91] FerryKV, Hamilton TC, JohnsonSW. Increased nucleotide excision repair in cisplatin-resistant ovarian cancer cells: role of ERCC1-XPF. Biochem Pharmacol. 2000; 60(9): 1305-1313.

[92] ShivjiMK, PodustVN, HubscherU, Wood RD. Nucleotide excision repair DNA synthesis by DNA polymerase epsilon in the presence of PCNA, RFC, and RPA. Biochemistry. 1995; 34(15): 5011-5017.

[93] MuzammalM, AliMZ, AhmadS, et al. The molecular genetics of UV-Sensitive syndrome: a rare dermal anomaly. J Pak Med Assoc. 2021; 71(10): 2391-2396.

[94] NataleV, RaquerH. Xeroderma pigmentosum-Cockayne syndrome complex. Orphanet J Rare Dis. 2017; 12(1): 65.

[95] BlackJO. Xeroderma pigmentosum. Head Neck Pathol. 2016; 10(2): 139-144.

[96] MacerelliM, Ganzinelli M, GouedardC, et al. Can the response to a platinum-based therapy be predicted by the DNA repair status in non-small cell lung cancer? Cancer Treat Rev. 2016; 48: 8-19.

[97] DamiaG, Imperatori L, StefaniniM, D’IncalciM. Sensitivity of CHO mutant cell lines with specific defects in nucleotide excision repair to different anti-cancer agents. Int J Cancer. 1996; 66(6): 779-783.

[98] AroraS, Kothandapani A, TillisonK, Kalman-MalteseV, Patrick SM. Downregulation of XPF-ERCC1 enhances cisplatin efficacy in cancer cells. DNA Repair. 2010; 9(7): 745-753.

[99] Cancer Genome Atlas ResearchNetwork. Integrated genomic analyses of ovarian carcinoma. Nature. 2011; 474(7353): 609-615.

[100] KonstantinopoulosPA, Ceccaldi R, ShapiroGI, D’AndreaAD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015; 5(11): 1137-1154.

[101] Pajuelo-LozanoN, Bargiela-Iparraguirre J, DominguezG, QuirogaAG, PeronaR, Sanchez-Perez IXPA, XPC, and XPD modulate sensitivity in gastric cisplatin resistance cancer cells. Front Pharmacol. 2018; 9: 1197.

[102] ZhangY, CaoJ, MengY, Qu C, ShenF, XuL. Overexpression of xeroderma pigmentosum group C decreases the chemotherapeutic sensitivity of colorectal carcinoma cells to cisplatin. Oncol Lett. 2018; 15(5): 6336-6344.

[103] ChiappaM, Guffanti F, GrasselliC, et al. Different patterns of platinum resistance in ovarian cancer cells with homologous recombination proficient and deficient background. Int J Mol Sci. 2024; 25(5).

[104] StinsonBM, LoparoJJ. Repair of DNA double-strand breaks by the nonhomologous end joining pathway. Annu Rev Biochem. 2021; 90: 137-164.

[105] SchrempfA, Slyskova J, LoizouJI. Targeting the DNA repair enzyme polymerase theta in cancer therapy. Trends Cancer. 2021; 7(2): 98-111.

[106] DingQ, ReddyYV, WangW, et al. Autophosphorylation of the catalytic subunit of the DNA-dependent protein kinase is required for efficient end processing during DNA double-strand break repair. Mol Cell Biol. 2003; 23(16): 5836-5848.

[107] MeekK, Douglas P, CuiX, DingQ, Lees-Miller SP. Trans autophosphorylation at DNA-dependent protein kinase’s two major autophosphorylation site clusters facilitates end processing but not end joining. Mol Cell Biol. 2007; 27(10): 3881-3890.

[108] LieberMR. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem. 2010; 79: 181-211.

[109] DamiaG. Targeting DNA-PK in cancer. Mutat Res. 2020; 821: 111692.

[110] BlackfordAN, Jackson SP. ATM, ATR, and DNA-PK: the Trinity at the heart of the DNA damage response. Mol Cell. 2017; 66(6): 801-817.

[111] MylerLR, Gallardo IF, SoniatMM, et al. Single-molecule imaging reveals how Mre11-Rad50-Nbs1 initiates DNA break repair. Mol Cell. 2017; 67(5): 891-898.

[112] SunY, McCorvie TJ, YatesLA, ZhangX. Structural basis of homologous recombination. Cell Mol Life Sci. 2020; 77(1): 3-18.

[113] ScullyR, PandayA, ElangoR, Willis NA. DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat Rev Mol Cell Biol. 2019; 20(11): 698-714.

[114] Carvajal-GarciaJ, Cho JE, Carvajal-GarciaP, et al. Mechanistic basis for microhomology identification and genome scarring by polymerase theta. Proc Natl Acad Sci U S A. 2020; 117(15): 8476-8485.

[115] KruchininAA, Makarova AV. Multifaceted nature of DNA polymerase theta. Int J Mol Sci. 2023; 24(4): 3619.

[116] DrzewieckaM, Barszczewska-Pietraszek G, CzarnyP, SkorskiT, Sliwinski T. Synthetic lethality targeting poltheta. Genes. 2022; 13(6): 1101.

[117] ZatreanuD, Robinson HMR, AlkhatibO, et al. Poltheta inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nat Commun. 2021; 12(1): 3636.

[118] ZelenskyAN, Schimmel J, KoolH, KanaarR, Tijsterman M. Inactivation of Pol theta and C-NHEJ eliminates off-target integration of exogenous DNA. Nat Commun. 2017; 8(1): 66.

[119] CeccaldiR, Rondinelli B, D’AndreaAD. Repair pathway choices and consequences at the double-strand break. Trends Cell Biol. 2016; 26(1): 52-64.

[120] RamsdenDA, Carvajal-Garcia J, GuptaGP. Mechanism, cellular functions and cancer roles of polymerase-theta-mediated DNA end joining. Nat Rev Mol Cell Biol. 2022; 23(2): 125-140.

[121] SfeirA, Symington LS. Microhomology-mediated end joining: a back-up survival mechanism or dedicated pathway? Trends Biochem Sci. 2015; 40(11): 701-714.

[122] BrambatiA, BarryRM, SfeirA. DNA polymerase theta (Poltheta)—an error-prone polymerase necessary for genome stability. Curr Opin Genet Dev. 2020; 60: 119-126.

[123] DeganP, Cappelli E, RegisS, RaveraS. New insights and perspectives in Fanconi anemia research. Trends Mol Med. 2019; 25(3): 167-170.

[124] DeansAJ, WestSC. DNA interstrand crosslink repair and cancer. Nat Rev Cancer. 2011; 11(7): 467-480.

[125] CeccaldiR, Sarangi P, D’AndreaAD. The Fanconi anaemia pathway: new players and new functions. Nat Rev Mol Cell Biol. 2016; 17(6): 337-349.

[126] Fiesco-RoaMO, Garcia-de Teresa B, Leal-AnayaP, et al. Fanconi anemia and dyskeratosis congenita/telomere biology disorders: two inherited bone marrow failure syndromes with genomic instability. Front Oncol. 2022; 12: 949435.

[127] PaceP, Mosedale G, HodskinsonMR, RosadoIV, Sivasubramaniam M, PatelKJ. Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway. Science. 2010; 329(5988): 219-223.

[128] OvejeroS, BuenoA, SacristanMP. Working on genomic stability: from the S-phase to mitosis. Genes. 2020; 11(2): 225.

[129] ThakarT, Moldovan GL. The emerging determinants of replication fork stability. Nucleic Acids Res. 2021; 49(13): 7224-7238.

[130] KunkelTA, ErieDA. Eukaryotic mismatch repair in relation to DNA replication. Annu Rev Genet. 2015; 49: 291-313.

[131] NemethE, SzutsD. The mutagenic consequences of defective DNA repair. DNA Repair. 2024; 139: 103694.

[132] FurmanCM, Elbashir R, AlaniE. Expanded roles for the MutL family of DNA mismatch repair proteins. Yeast. 2021; 38(1): 39-53.

[133] HsiehP, ZhangY. The Devil is in the details for DNA mismatch repair. Proc Natl Acad Sci U S A. 2017; 114(14): 3552-3554.

[134] BarettiM, LeDT. DNA mismatch repair in cancer. Pharmacol Ther. 2018; 189: 45-62.

[135] BillerLH, SyngalS, YurgelunMB. Recent advances in Lynch syndrome. Fam Cancer. 2019; 18(2): 211-219.

[136] KanekoE, SatoN, SugawaraT, et al. MLH1 promoter hypermethylation predicts poorer prognosis in mismatch repair deficiency endometrial carcinomas. J Gynecol Oncol. 2021; 32(6): e79.

[137] WestwoodA, GloverA, HutchinsG, et al. Additional loss of MSH2 and MSH6 expression in sporadic deficient mismatch repair colorectal cancer due to MLH1 promoter hypermethylation. J Clin Pathol. 2019; 72(6): 443-447.

[138] UlrichHD. Conservation of DNA damage tolerance pathways from yeast to humans. Biochem Soc Trans. 2007; 35: 1334-1337.

[139] AriannaGA, Korzhnev DM. Protein assemblies in translesion synthesis. Genes. 2024; 15(7): 832.

[140] SaleJE, Lehmann AR, WoodgateR. Y-family DNA polymerases and their role in tolerance of cellular DNA damage. Nat Rev Mol Cell Biol. 2012; 13(3): 141-152.

[141] VaismanA, Woodgate R. Translesion DNA polymerases in eukaryotes: what makes them tick? Crit Rev Biochem Mol Biol. 2017; 52(3): 274-303.

[142] WatersLS, Minesinger BK, WiltroutME, D’SouzaS, Woodruff RV, WalkerGC. Eukaryotic translesion polymerases and their roles and regulation in DNA damage tolerance. Microbiol Mol Biol Rev. 2009; 73(1): 134-154.

[143] Reha-KrantzLJ. DNA polymerase proofreading: multiple roles maintain genome stability. Biochim Biophys Acta. 2010; 1804(5): 1049-1063.

[144] YangW, GaoY. Translesion and repair DNA polymerases: diverse structure and mechanism. Annu Rev Biochem. 2018; 87: 239-261.

[145] JainR, Aggarwal AK, RechkoblitO. Eukaryotic DNA polymerases. Curr Opin Struct Biol. 2018; 53: 77-87.

[146] PrevitaliV, Bagnolini G, CiamaroneA, et al. New horizons of synthetic lethality in cancer: current development and future perspectives. J Med Chem. 2024; 67(14): 11488-11521.

[147] ArcieriM, TiusV, AndreettaC, et al. How BRCA and homologous recombination deficiency change therapeutic strategies in ovarian cancer: a review of literature. Front Oncol. 2024; 14: 1335196.

[148] CunninghamML, Schiewer MJ. PARP-ish: gaps in molecular understanding and clinical trials targeting PARP exacerbate racial disparities in prostate cancer. Cancer Res. 2024; 84(13): 2049-2059.

[149] McCabeN, HannaC, WalkerSM, et al. Mechanistic rationale to target PTEN-deficient tumor cells with inhibitors of the DNA damage response kinase ATM. Cancer Res. 2015; 75(11): 2159-2165.

[150] SmidaM, de la Cruz FF, KerzendorferC, et al. MEK inhibitors block growth of lung tumours with mutations in ataxia-telangiectasia mutated. Nat Commun. 2016; 7: 13701.

[151] WangC, JetteN, MoussienkoD, Bebb DG, Lees-MillerSP. ATM-deficient colorectal cancer cells are sensitive to the PARP inhibitor olaparib. Transl Oncol. 2017; 10(2): 190-196.

[152] DietleinF, ThelenL, JokicM, et al. A functional cancer genomics screen identifies a druggable synthetic lethal interaction between MSH3 and PRKDC. Cancer Discov. 2014; 4(5): 592-605.

[153] KwokM, DaviesN, AgathanggelouA, et al. ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53-or ATM-defective chronic lymphocytic leukemia cells. Blood. 2016; 127(5): 582-595.

[154] KwokM, DaviesN, AgathanggelouA, et al. Synthetic lethality in chronic lymphocytic leukaemia with DNA damage response defects by targeting the ATR pathway. Lancet. 2015; 385(suppl 1): S58.

[155] MenezesDL, HoltJ, TangY, et al. A synthetic lethal screen reveals enhanced sensitivity to ATR inhibitor treatment in mantle cell lymphoma with ATM loss-of-function. Mol Cancer Res. 2015; 13(1): 120-129.

[156] MinA, ImSA, JangH, et al. A novel oral inhibitor of ATR, induces synthetic lethality with ATM deficiency in gastric cancer cells. Mol Cancer Ther. 2017; 16(4): 566-577.

[157] DaiCH, ChenP, LiJ, et al. Co-inhibition of pol theta and HR genes efficiently synergize with cisplatin to suppress cisplatin-resistant lung cancer cells survival. Oncotarget. 2016; 7(40): 65157-65170.

[158] Patterson-FortinJ, D’Andrea AD. Exploiting the microhomology-mediated end-joining pathway in cancer therapy. Cancer Res. 2020; 80(21): 4593-4600.

[159] CeccaldiR, LiuJC, AmunugamaR, et al. Homologous-recombination-deficient tumours are dependent on Poltheta-mediated repair. Nature. 2015; 518(7538): 258-262.

[160] Mateos-GomezPA, GongF, NairN, Miller KM, Lazzerini-DenchiE, SfeirA. Mammalian polymerase theta promotes alternative NHEJ and suppresses recombination. Nature. 2015; 518(7538): 254-257.

[161] WoodRD, Doublie S. Genome protection by DNA polymerase theta. Annu Rev Genet. 2022; 56: 207-228.

[162] ZhouJ, GelotC, PantelidouC, et al. A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors. Nat Cancer. 2021; 2(6): 598-610.

[163] FengW, Simpson DA, Carvajal-GarciaJ, et al. Genetic determinants of cellular addiction to DNA polymerase theta. Nat Commun. 2019; 10(1): 4286.

[164] VekariyaU, TomaM, Nieborowska-SkorskaM, et al. DNA polymerase theta protects leukemia cells from metabolically induced DNA damage. Blood. 2023; 141(19): 2372-2389.

[165] YousefzadehMJ, WyattDW, TakataK, et al. Mechanism of suppression of chromosomal instability by DNA polymerase POLQ. PLoS Genet. 2014; 10(10): e1004654.

[166] WangZ, SongY, LiS, et al. DNA polymerase theta (POLQ) is important for repair of DNA double-strand breaks caused by fork collapse. J Biol Chem. 2019; 294(11): 3909-3919.

[167] Rodriguez-BerrigueteG, Ranzani M, PrevoR, et al. Small-molecule poltheta inhibitors provide safe and effective tumor radiosensitization in preclinical models. Clin Cancer Res. 2023; 29(8): 1631-1642.

[168] RaoX, XingB, WuZ, et al. Targeting polymerase theta impairs tumorigenesis and enhances radiosensitivity in lung adenocarcinoma. Cancer Sci. 2023; 114(5): 1943-1957.

[169] ZimmermannA, ZenkeFT, ChiuLY, et al. A new class of selective ATM inhibitors as combination partners of DNA double-strand break inducing cancer therapies. Mol Cancer Ther. 2022; 21(6): 859-870.

[170] WaqarSN, Robinson C, OlszanskiAJ, et al. Phase I trial of ATM inhibitor M3541 in combination with palliative radiotherapy in patients with solid tumors. Invest New Drugs. 2022; 40(3): 596-605.

[171] SiuLL, YapTA, GentaS, et al. Abstract CT171: a first-in-human phase I study of the ATM inhibitor M4076 in patients with advanced solid tumors (DDRiver Solid Tumors 410): part 1A results. Cancer Res. 2023; 83(8_suppl):CT171.

[172] SiuLL, Cabanas EG, BoniV, et al. Abstract CT063: phase Ib trial of ATR inhibitor (ATRi) tuvusertib + ATM inhibitor (ATMi) lartesertib (M4076) in patients (pts) with advanced solid tumors. Cancer Res. 2024; 84(7): CT063.

[173] GilmerTM, LaiCH, GuoK, et al. A novel dual ATM/DNA-PK inhibitor, XRD-0394, potently radiosensitizes and potentiates PARP and topoisomerase I inhibitors. Mol Cancer Ther. 2024; 23(6): 751-765.

[174] RichesLC, Trinidad AG, HughesG, et al. Pharmacology of the ATM inhibitor AZD0156: potentiation of irradiation and olaparib responses preclinically. Mol Cancer Ther. 2020; 19(1): 13-25.

[175] DavisSL, Hartman SJ, BagbySM, et al. ATM kinase inhibitor AZD0156 in combination with irinotecan and 5-fluorouracil in preclinical models of colorectal cancer. BMC Cancer. 2022; 22(1): 1107.

[176] AbidaW, BangYJ, CarterL, et al. Abstract A094: phase I modular study of AZD0156, a first-in-class oral selective inhibitor of ataxia telangiectasia mutated protein kinase (ATM), in combination with olaparib (AToM Study, Module 1). Mol Cancer Therap. 2018; 17(1_suppl): A094.

[177] DurantST, ZhengL, WangY, et al. The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models. Sci Adv. 2018; 4(6): eaat1719.

[178] ChenJ, Laverty DJ, TaleleS, et al. Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization. Sci Transl Med. 2024; 16(734): eadj5962.

[179] TumaAM, ZhongW, LiuL, et al. Abstract 3305: wSD-0628, a novel brain penetrant ATM inhibitor, radiosensitizes GBM and melanoma patient derived xenografts. Cancer Res. 2022; 82(12_suppl): 3305-3305.

[180] BarniehFM, Loadman PM, FalconerRA. Progress towards a clinically-successful ATR inhibitor for cancer therapy. Curr Res Pharmacol Drug Discov. 2021; 2: 100017.

[181] GralewskaP, GajekA, RybaczekD, Marczak A, RogalskaA. The influence of PARP, ATR, CHK1 inhibitors on premature mitotic entry and genomic instability in high-grade serous BRCA(MUT) and BRCA(WT) ovarian cancer cells. Cells. 2022; 11(12): 1889.

[182] SorensenCS, HansenLT, DziegielewskiJ, et al. The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair. Nat Cell Biol. 2005; 7(2): 195-201.

[183] de KleinA, Muijtjens M, van OsR, et al. Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice. Curr Biol. 2000; 10(8): 479-482.

[184] FokasE, PrevoR, HammondEM, Brunner TB, McKennaWG, MuschelRJ. Targeting ATR in DNA damage response and cancer therapeutics. Cancer Treat Rev. 2014; 40(1): 109-117.

[185] MartoranaF, Da Silva LA, SessaC, ColomboI. Everything comes with a price: the toxicity profile of DNA-damage response targeting agents. Cancers. 2022; 14(4): 953.

[186] DillonMT, Guevara J, MohammedK, et al. Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation. J Clin Invest. 2024; 134(2): e175369.

[187] YapTA, O’Carrigan B, PenneyMS, et al. Phase I trial of first-in-class ATR inhibitor M6620 (VX-970) as monotherapy or in combination with carboplatin in patients with advanced solid tumors. J Clin Oncol. 2020; 38(27): 3195-3204.

[188] TolcherAW, YapTA, PlummerR, et al. Translational analyses of ATR inhibitor M1774 in a Phase I study in patients with solid tumors (DDRiver Solid Tumors 301). Cancer Res. 2023; 83(8_Supplement): CT271.

[189] CharrierJD, Durrant SJ, GolecJM, et al. Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. J Med Chem. 2011; 54(7): 2320-2330.

[190] ReaperPM, Griffiths MR, LongJM, et al. Selective killing of ATM-or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol. 2011; 7(7): 428-430.

[191] HallAB, Newsome D, WangY, et al. Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970. Oncotarget. 2014; 5(14): 5674-5685.

[192] KurmashevaRT, Kurmashev D, ReynoldsCP, et al. Initial testing (stage 1) of M6620 (formerly VX-970), a novel ATR inhibitor, alone and combined with cisplatin and melphalan, by the pediatric preclinical testing program. Pediatr Blood Cancer. 2018; 65(2).

[193] LeszczynskaKB, Dobrynin G, LeslieRE, et al. Preclinical testing of an Atr inhibitor demonstrates improved response to standard therapies for esophageal cancer. Radiother Oncol. 2016; 121(2): 232-238.

[194] TuX, KahilaMM, ZhouQ, et al. ATR inhibition is a promising radiosensitizing strategy for triple-negative breast cancer. Mol Cancer Ther. 2018; 17(11): 2462-2472.

[195] MiddletonMR, DeanE, EvansTRJ, et al. Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours. Br J Cancer. 2021; 125(4): 510-519.

[196] PlummerR, DeanE, ArkenauHT, et al. A phase 1b study evaluating the safety and preliminary efficacy of berzosertib in combination with gemcitabine in patients with advanced non-small cell lung cancer. Lung Cancer. 2022; 163: 19-26.

[197] ShapiroGI, Wesolowski R, DevoeC, et al. Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours. Br J Cancer. 2021; 125(4): 520-527.

[198] TelliML, Tolaney SM, ShapiroGI, et al. Phase 1b study of berzosertib and cisplatin in patients with advanced triple-negative breast cancer. NPJ Breast Cancer. 2022; 8(1): 45.

[199] ThomasA, RedonCE, SciutoL, et al. Phase I study of ATR inhibitor M6620 in combination with topotecan in patients with advanced solid tumors. J Clin Oncol. 2018; 36(16): 1594-1602.

[200] JavedSR, LordS, El BadriS, et al. CHARIOT: a phase I study of berzosertib with chemoradiotherapy in oesophageal and other solid cancers using time to event continual reassessment method. Br J Cancer. 2024; 130(3): 467-475.

[201] KonstantinopoulosPA, Cheng SC, et al. Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020; 21(7): 957-968.

[202] KonstantinopoulosPA, Cheng SC, LeeEK, et al. Randomized phase II study of gemcitabine with or without ATR inhibitor berzosertib in platinum-resistant ovarian cancer: final overall survival and biomarker analyses. JCO Precis Oncol. 2024; 8: e2300635.

[203] KonstantinopoulosPA, da Costa A, GulhanD, et al. A replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer. Nat Commun. 2021; 12(1): 5574.

[204] MittraA, CoyneGHOS, DoKT, et al. Safety and tolerability of veliparib, an oral PARP inhibitor, and M6620 (VX-970), an ATR inhibitor, in combination with cisplatin in patients with refractory solid tumors. J Clin Oncol. 2019; 37(15): 3067-3067.

[205] BesseB, CastroG, FelipE, et al. LATIFY: phase 3 study of ceralasertib + durvalumab vs docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer that progressed on or after anti-PD-(L)1 and platinum-based therapy. J Clin Oncol. 2023; 41(16): TPS9161.

[206] KimR, KwonM, AnM, et al. Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced/metastatic melanoma who have failed prior anti-PD-1 therapy. Ann Oncol. 2022; 33(2): 193-203.

[207] KwonM, KimG, KimR, et al. Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced gastric cancer. J Immunother Cancer. 2022; 10(7): e005041.

[208] BesseB, Pons-Tostivint E, ParkK, et al. Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial. Nat Med. 2024; 30(3): 716-729.

[209] HardakerEL, Sanseviero E, KarmokarA, et al. The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment. Nat Commun. 2024; 15(1): 1700.

[210] WilsonZ, OdedraR, WallezY, et al. ATR inhibitor AZD6738 (Ceralasertib) exerts antitumor activity as a monotherapy and in combination with chemotherapy and the PARP inhibitor olaparib. Cancer Res. 2022; 82(6): 1140-1152.

[211] KimH, XuH, GeorgeE, et al. Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models. Nat Commun. 2020; 11(1): 3726.

[212] ShahPD, Wethington SL, PaganC, et al. Combination ATR and PARP inhibitor (CAPRI): a phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-resistant epithelial ovarian cancer. Gynecol Oncol. 2021; 163(2): 246-253.

[213] ParkS, KimYJ, MinYJ, et al. Biomarker-driven phase 2 umbrella trial: clinical efficacy of olaparib monotherapy and combination with ceralasertib (AZD6738) in small cell lung cancer. Cancer. 2024; 130(4): 541-552.

[214] WethingtonSL, ShahPD, MartinL, et al. Combination ATR (ceralasertib) and PARP (olaparib) inhibitor (CAPRI) trial in acquired PARP inhibitor-resistant homologous recombination-deficient ovarian cancer. Clin Cancer Res. 2023; 29(15): 2800-2807.

[215] RoulstonA, Zimmermann M, PappR, et al. RP-3500: a novel, potent, and selective ATR inhibitor that is effective in preclinical models as a monotherapy and in combination with PARP inhibitors. Mol Cancer Ther. 2022; 21(2): 245-256.

[216] BlackWC, AbdoliA, AnX, et al. Discovery of the potent and selective ATR inhibitor camonsertib (RP-3500). J Med Chem. 2024; 67(4): 2349-2368.

[217] XuH, GeorgeE, GalloD, et al. Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR. Res Sq. 2024.

[218] YapTA, SchramA, LeeEK, et al. Abstract PR008: mYTHIC: first-in-human (FIH) biomarker-driven phase I trial of PKMYT1 inhibitor lunresertib (lunre) alone and with ATR inhibitor camonsertib (cam) in solid tumors with CCNE1 amplification or deleterious alterations in FBXW7 or PPP2R1A. Mol Cancer Therap. 2023; 22(12): PR008.

[219] YapTA, Fontana E, LeeEK, et al. Camonsertib in DNA damage response-deficient advanced solid tumors: phase 1 trial results. Nat Med. 2023; 29(6): 1400-1411.

[220] ManavellaDD, McNamara B, HaroldJ, et al. Ovarian and uterine carcinosarcomas are sensitive in vitro and in vivo to elimusertib, a novel ataxia-telangiectasia and Rad3-related (ATR) kinase inhibitor. Gynecol Oncol. 2023; 169: 98-105.

[221] WengnerAM, Siemeister G, LuckingU, et al. The novel ATR inhibitor BAY 1895344 is efficacious as monotherapy and combined with DNA damage-inducing or repair-compromising therapies in preclinical cancer models. Mol Cancer Ther. 2020; 19(1): 26-38.

[222] PuschFF, GarciaHD, XuR, et al. Elimusertib has antitumor activity in preclinical patient-derived pediatric solid tumor models. Mol Cancer Ther. 2024; 23(4): 507-519.

[223] OrtizMV, BenderJLG, MinardCG, et al. A phase 1/2 study of bay 18953444 (Elimusertib) in pediatric patients with relapsed or refractory solid tumors: initial report of the phase 1 results of PEPN2112. J Clin Oncol. 2023; 41(16): e15131.

[224] MoweryYM, Niedzwiecki D, ChoeJH, KirschDG, BrizelDM. Phase I trial of the ATR inhibitor BAY 1895344 combined with stereotactic body radiation therapy and pembrolizumab for recurrent head and neck squamous cell carcinoma. J Clin Oncol. 2022; 40(16): TPS6108.

[225] JoU, Senatorov IS, ZimmermannA, et al. Novel and highly potent ATR inhibitor M4344 kills cancer cells with replication stress, and enhances the chemotherapeutic activity of widely used DNA damaging agents. Mol Cancer Ther. 2021; 20(8): 1431-1441.

[226] BurrisHA, BerlinJ, ArkenauT, et al. A phase I study of ATR inhibitor gartisertib (M4344) as a single agent and in combination with carboplatin in patients with advanced solid tumours. Br J Cancer. 2024; 130(7): 1131-1140.

[227] JoU, Arakawa Y, ZimmermannA, et al. The novel ATR inhibitor M1774 induces replication protein overexpression and broad synergy with DNA-targeted anticancer drugs. Mol Cancer Ther. 2024; 23(7): 911-923.

[228] YapTA, Tolcher AW, PlummerR, et al. First-in-human study of the ataxia telangiectasia and Rad3-related (ATR) inhibitor tuvusertib (M1774) as monotherapy in patients with solid tumors. Clin Cancer Res. 2024; 30(10): 2057-2067.

[229] MajithiyaJB, Luzarraga MR, NewmanR, et al. Abstract 312: the ATR inhibitor ART0380 shows preclinical efficacy in monotherapy or in combination with gemcitabine, aPD1, PARP inhibitors and topoisomerase 1 poisons. Cancer Res. 2023; 83(7_suppl): 312.

[230] MooreK, PatelMR, FalchookGS, et al. 680P First results from the phase I trial of the ATR inhibitor, ART0380, in advanced solid tumors. Ann Oncol. 2023; 34: S475-S476.

[231] SimpkinsF, Mahipal A, LoRussoP, et al. Abstract CT196: first-in-human phase 1/2a trial of a macrocyclic ATR inhibitor (ATRN-119) in patients with advanced solid tumors. Cancer Res. 2024; 84(7_suppl):CT196.

[232] GuptaN, HuangTT, HoribataS, Lee JM. Cell cycle checkpoints and beyond: exploiting the ATR/CHK1/WEE1 pathway for the treatment of PARP inhibitor-resistant cancer. Pharmacol Res. 2022; 178: 106162.

[233] JiangK, DengM, DuW, LiuT, LiJ, ZhouY. Functions and inhibitors of CHK1 in cancer therapy. Med Drug Discov. 2024; 22: 100185.

[234] MahrusS, DuPreeK, KowanetzK, et al. Abstract 944: development of predictive and pharmacodynamic biomarker strategies for GDC-0425, a checkpoint kinase 1 inhibitor, in combination with gemcitabine. Cancer Res. 2015; 75: 944-944.

[235] InfanteJR, Hollebecque A, Postel-VinayS, et al. Phase I study of GDC-0425, a checkpoint kinase 1 inhibitor, in combination with gemcitabine in patients with refractory solid tumors. Clin Cancer Res. 2017; 23(10): 2423-2432.

[236] ItalianoA, Infante JR, ShapiroGI, et al. Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine in patients with refractory solid tumors. Ann Oncol. 2018; 29(5): 1304-1311.

[237] ZhouZR, YangZZ, WangSJ, et al. The Chk1 inhibitor MK-8776 increases the radiosensitivity of human triple-negative breast cancer by inhibiting autophagy. Acta Pharmacol Sin. 2017; 38(4): 513-523.

[238] KarpJE, ThomasBM, GreerJM, et al. Phase I and pharmacologic trial of cytosine arabinoside with the selective checkpoint 1 inhibitor Sch 900776 in refractory acute leukemias. Clin Cancer Res. 2012; 18(24): 6723-6731.

[239] DaudAI, Ashworth MT, StrosbergJ, et al. Phase I dose-escalation trial of checkpoint kinase 1 inhibitor MK-8776 as monotherapy and in combination with gemcitabine in patients with advanced solid tumors. J Clin Oncol. 2015; 33(9): 1060-1066.

[240] WebsterJA, TibesR, MorrisL, et al. Randomized phase II trial of cytosine arabinoside with and without the CHK1 inhibitor MK-8776 in relapsed and refractory acute myeloid leukemia. Leuk Res. 2017; 61: 108-116.

[241] CalvoE, Braiteh F, Von HoffD, et al. Phase I study of CHK1 inhibitor LY2603618 in combination with gemcitabine in patients with solid tumors. Oncology. 2016; 91(5): 251-260.

[242] CalvoE, ChenVJ, MarshallM, et al. Preclinical analyses and phase I evaluation of LY2603618 administered in combination with pemetrexed and cisplatin in patients with advanced cancer. Invest New Drugs. 2014; 32(5): 955-968.

[243] DoiT, Yoshino T, ShitaraK, et al. Phase I study of LY2603618, a CHK1 inhibitor, in combination with gemcitabine in Japanese patients with solid tumors. Anticancer Drugs. 2015; 26(10): 1043-1053.

[244] LaquenteB, Lopez-Martin J, RichardsD, et al. A phase II study to evaluate LY2603618 in combination with gemcitabine in pancreatic cancer patients. BMC Cancer. 2017; 17(1): 137.

[245] ScagliottiG, KangJH, SmithD, et al. Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer. Invest New Drugs. 2016; 34(5): 625-635.

[246] WehlerT, ThomasM, SchumannC, et al. A randomized, phase 2 evaluation of the CHK1 inhibitor, LY2603618, administered in combination with pemetrexed and cisplatin in patients with advanced nonsquamous non-small cell lung cancer. Lung Cancer. 2017; 108: 212-216.

[247] ManiC, Jonnalagadda S, LingareddyJ, AwasthiS, Gmeiner WH, PalleK. Prexasertib treatment induces homologous recombination deficiency and synergizes with olaparib in triple-negative breast cancer cells. Breast Cancer Res. 2019; 21(1): 104.

[248] ParmarK, Kochupurakkal BS, LazaroJB, 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): 6127-6140.

[249] MooreKN, HongDS, PatelMR, et al. A phase 1b trial of prexasertib in combination with standard-of-care agents in advanced or metastatic cancer. Target Oncol. 2021; 16(5): 569-589.

[250] DoKT, Kochupurakkal B, KellandS, et al. Phase 1 combination study of the CHK1 inhibitor prexasertib and the PARP inhibitor olaparib in high-grade serous ovarian cancer and other solid tumors. Clin Cancer Res. 2021; 27(17): 4710-4716.

[251] KonstantinopoulosPA, Lee JM, GaoB, et al. A phase 2 study of prexasertib (LY2606368) in platinum resistant or refractory recurrent ovarian cancer. Gynecol Oncol. 2022; 167(2): 213-225.

[252] GiudiceE, HuangTT, NairJR, et al. The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial. Nat Commun. 2024; 15(1): 2805.

[253] HuffmanBM, FengH, ParmarK, et al. A phase I expansion cohort study evaluating the safety and efficacy of the CHK1 inhibitor LY2880070 with low-dose gemcitabine in patients with metastatic pancreatic adenocarcinoma. Clin Cancer Res. 2023; 29(24): 5047-5056.

[254] XuH, GittoSB, HoGY, et al. CHK1 inhibitor SRA737 is active in PARP inhibitor resistant and CCNE1 amplified ovarian cancer. iScience. 2024; 27(7): 109978.

[255] KristeleitR, Plummer R, JonesR, et al. A phase 1/2 trial of SRA737 (a Chk1 inhibitor) administered orally in patients with advanced cancer. Br J Cancer. 2023; 129(1): 38-45.

[256] JonesR, Plummer R, MorenoV, et al. A phase I/II trial of oral SRA737 (a Chk1 inhibitor) given in combination with low-dose gemcitabine in patients with advanced cancer. Clin Cancer Res. 2023; 29(2): 331-340.

[257] AlliVJ, YadavP, SureshV, Jadav SS. Synthetic and medicinal chemistry approaches toward WEE1 kinase inhibitors and its degraders. ACS Omega. 2023; 8(23): 20196-20233.

[258] ZhangC, PengK, LiuQ, HuangQ, LiuT. Adavosertib and beyond: biomarkers, drug combination and toxicity of WEE1 inhibitors. Crit Rev Oncol Hematol. 2024; 193: 104233.

[259] HiraiH, Iwasawa Y, OkadaM, et al. Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol Cancer Ther. 2009; 8(11): 2992-3000.

[260] GuertinAD, LiJ, LiuY, et al. Preclinical evaluation of the WEE1 inhibitor MK-1775 as single-agent anticancer therapy. Mol Cancer Ther. 2013; 12(8): 1442-1452.

[261] RajeshkumarNV, De Oliveira E, OttenhofN, et al. MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts. Clin Cancer Res. 2011; 17(9): 2799-2806.

[262] SanaiN, LiJ, BoernerJ, et al. Phase 0 trial of AZD1775 in first-recurrence glioblastoma patients. Clin Cancer Res. 2018; 24(16): 3820-3828.

[263] DoK, Wilsker D, JiJ, et al. Phase I study of single-agent AZD1775 (MK-1775), a Wee1 kinase inhibitor, in patients with refractory solid tumors. J Clin Oncol. 2015; 33(30): 3409-3415.

[264] LiuJF, XiongN, CamposSM, et al. Phase II study of the WEE1 inhibitor adavosertib in recurrent uterine serous carcinoma. J Clin Oncol. 2021; 39(14): 1531-1539.

[265] CuneoKC, MorganMA, SahaiV, et al. Dose escalation trial of the Wee1 inhibitor adavosertib (AZD1775) in combination with gemcitabine and radiation for patients with locally advanced pancreatic cancer. J Clin Oncol. 2019; 37(29): 2643-2650.

[266] LeijenS, van Geel RM, SonkeGS, et al. Phase II study of WEE1 inhibitor AZD1775 plus carboplatin in patients with TP53-mutated ovarian cancer refractory or resistant to first-line therapy within 3 months. J Clin Oncol. 2016; 34(36): 4354-4361.

[267] HuangPQ, BorenBC, HegdeSG, et al. Discovery of ZN-c3, a highly potent and selective wee1 inhibitor undergoing evaluation in clinical trials for the treatment of cancer. J Med Chem. 2021; 64(17): 13004-13024.

[268] MaJ, LiuW, ChungH, et al. Abstract 2153: cyclin E1 protein overexpression sensitizes ovarian cancer cells to ZN-c3, a novel, selective and oral bioavailable inhibitor of Wee1. Cancer Res. 2023; 83(7_suppl): 2153.

[269] GelderblomH, Jalving M, DesarI, et al. Debio 0123-101: a phase 1 trial of Debio 0123 in combination with carboplatin in advanced solid tumors—safety, pharmacokinetic, and preliminary antitumor activity data. J Clin Oncol. 2023; 41(16): 3012.

[270] LinC-C, GrewalJS, SommerhalderD, et al. A phase 1 dose-escalation and -expansion study of IMP7068, a WEE1 inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2022; 40(16): e15052.

[271] PapadopoulosKP, SharmaM, DummerR, et al. Results of a phase 1, dose-finding study of Debio 0123 as monotherapy in adult patients with advanced solid tumors: safety, pharmacokinetic, and preliminary antitumor activity data. J Clin Oncol. 2024; 42(16_suppl): 3120.

[272] YangC, LiZ, LiQ, et al. Preclinical evaluation of SC0191, a small molecule inhibitor of Wee1 kinase. J Clin Oncol. 2020; 38(15_suppl):e15637.

[273] GalloD, YoungJTF, FourtounisJ, et al. CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition. Nature. 2022; 604(7907): 749-756.

[274] BubenikM, MaderP, MochirianP, et al. Identification of RP-6685, an orally bioavailable compound that inhibits the DNA polymerase activity of poltheta. J Med Chem. 2022; 65(19): 13198-13215.

[275] PismataroMC, Astolfi A, BarrecaML, et al. Small molecules targeting DNA polymerase theta (POLtheta) as promising synthetic lethal agents for precision cancer therapy. J Med Chem. 2023; 66(10): 6498-6522.

[276] StockleyML, Ferdinand A, BenedettiG, et al. Discovery, characterization, and structure-based optimization of small-molecule in vitro and in vivo probes for human DNA polymerase theta. J Med Chem. 2022; 65(20): 13879-13891.

[277] KennedyMJ, Armstrong DK, HuelskampAM, et al. Phase I and pharmacologic study of the alkylating agent modulator novobiocin in combination with high-dose chemotherapy for the treatment of metastatic breast cancer. J Clin Oncol. 1995; 13(5): 1136-1143.

[278] MurrenJR, DiStasio SA, LoricoA, et al. Phase I and pharmacokinetic study of novobiocin in combination with VP-16 in patients with refractory malignancies. Cancer J. 2000; 6(4): 256-265.

[279] Patterson-FortinJ, Bose A, TsaiWC, et al. Targeting DNA repair with combined inhibition of NHEJ and MMEJ induces synthetic lethality in TP53-mutant cancers. Cancer Res. 2022; 82(20): 3815-3829.

[280] ChiappaM, Guffanti F, BertoniF, ColomboI, DamiaG. Overcoming PARPi resistance: preclinical and clinical evidence in ovarian cancer. Drug Resist Updat. 2021; 55: 100744.

[281] CarrassaL, ChilaR, LupiM, et al. Combined inhibition of Chk1 and Wee1: in vitro synergistic effect translates to tumor growth inhibition in vivo. Cell Cycle. 2012; 11(13): 2507-2517.

[282] RestelliV, LupiM, ChilaR, et al. DNA damage response inhibitor combinations exert synergistic antitumor activity in aggressive B-cell lymphomas. Mol Cancer Ther. 2019; 18(7): 1255-1264.

[283] RestelliV, VagniM, ArribasAJ, Bertoni F, DamiaG, CarrassaL. Inhibition of CHK1 and WEE1 as a new therapeutic approach in diffuse large B cell lymphomas with MYC deregulation. Br J Haematol. 2018; 181(1): 129-133.

[284] PanD, WangQ, ShenA, Qi Z, ZhengC, HuB. When DNA damage responses meet tumor immunity: from mechanism to therapeutic opportunity. Int J Cancer. 2024; 155(3): 384-399.

[285] ChabanonRM, Rouanne M, LordCJ, SoriaJC, PaseroP, Postel-VinayS. Targeting the DNA damage response in immuno-oncology: developments and opportunities. Nat Rev Cancer. 2021; 21(11): 701-717.

[286] RonsonGE, Starowicz K, AnthonyEJ, et al. Mechanisms of synthetic lethality between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta targeting. Nat Commun. 2023; 14(1): 7834.

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