Exploiting DNA repair pathways for tumor sensitization, mitigation of resistance, and normal tissue protection in radiotherapy

Abstract

More than half of cancer patients are treated with radiotherapy, which kills tumor cells by directly and indirectly inducing DNA damage, including cytotoxic DNA double-strand breaks (DSBs). Tumor cells respond to these threats by activating a complex signaling network termed the DNA damage response (DDR). The DDR arrests the cell cycle, upregulates DNA repair, and triggers apoptosis when damage is excessive. The DDR signaling and DNA repair pathways are fertile terrain for therapeutic intervention. This review highlights strategies to improve therapeutic gain by targeting DDR and DNA repair pathways to radiosensitize tumor cells, overcome intrinsic and acquired tumor radioresistance, and protect normal tissue. Many biological and environmental factors determine tumor and normal cell responses to ionizing radiation and genotoxic chemotherapeutics. These include cell type and cell cycle phase distribution; tissue/tumor microenvironment and oxygen levels; DNA damage load and quality; DNA repair capacity; and susceptibility to apoptosis or other active or passive cell death pathways. We provide an overview of radiobiological parameters associated with X-ray, proton, and carbon ion radiotherapy; DNA repair and DNA damage signaling pathways; and other factors that regulate tumor and normal cell responses to radiation. We then focus on recent studies exploiting DSB repair pathways to enhance radiotherapy therapeutic gain.

Keywords

DNA repair / DNA double-strand break repair / non-homologous end-joining / homologous recombination / radiosensitization / radioprotection / cancer therapy

References

[1] Otter SJ,Devlin PM.Modern brachytherapy..Hematol Oncol Clin North Am2019;33:1011-25

[2] Daguenet E,Wozny AS.Radiation-induced bystander and abscopal effects: important lessons from preclinical models..Br J Cancer2020;123:339-48 PMCID:PMC7403362

[3] Halperin EC,Perez CA.2018;Lippincott Williams & Wilkins24

[4] Mounier NM,Wahdan SA,Azab SS.Chemotherapy-induced cognitive impairment (CICI): An overview of etiology and pathogenesis..Life Sci2020;258:118071

[5] Delou JMA,Souza LCM.Highlights in resistance mechanism pathways for combination therapy..Cells2019;8:1013 PMCID:PMC6770082

[6] Sato K,Imai T.Difference in acquired radioresistance induction between repeated photon and particle irradiation..Front Oncol2019;9:1213 PMCID:PMC6863406

[7] Ali MY,Noman ASM.Radioresistance in glioblastoma and the development of radiosensitizers..Cancers2020;12:2511 PMCID:PMC7564557

[8] Zhan Y.Multiple mechanisms involving in radioresistance of nasopharyngeal carcinoma..J Cancer2020;11:4193-204 PMCID:PMC7196263

[9] Thariat J,Sun Myint A,Gerard JP.Past, present, and future of radiotherapy for the benefit of patients..Nat Rev Clin Oncol2013;10:52-60

[10] Karpuz M,Ozer AY.Current and future approaches for effective cancer imaging and treatment..Cancer Biother Radiopharm2018;33:39-51

[11] Ramos P.Mechanism-based cancer therapy: resistance to therapy, therapy for resistance..Oncogene2015;34:3617-26

[12] Reisz JA,Qian J,Furdui CM.Effects of ionizing radiation on biological molecules--mechanisms of damage and emerging methods of detection..Antioxid Redox Signal2014;21:260-92 PMCID:PMC4060780

[13] Zou Z,Li H.Induction of reactive oxygen species: an emerging approach for cancer therapy..Apoptosis2017;22:1321-35

[14] Mailloux RJ.An Update on Mitochondrial Reactive Oxygen Species Production..Antioxidants2020;9:472 PMCID:PMC7346187

[15] Tubbs A.Endogenous DNA damage as a source of genomic instability in cancer..Cell2017;168:644-56 PMCID:PMC6591730

[16] Vilenchik MM.Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer..Proc Natl Acad Sci USA2003;100:12871-6 PMCID:PMC240711

[17] Mehta A.Sources of DNA double-strand breaks and models of recombinational DNA repair..Cold Spring Harb Perspect Biol2014;6:a016428 PMCID:PMC4142968

[18] Yang W.Translesion and repair DNA polymerases: diverse structure and mechanism..Annu Rev Biochem2018;87:239-61 PMCID:PMC6098713

[19] Allen C,Hromas R.More forks on the road to replication stress recovery..J Mol Cell Biol2011;3:4-12 PMCID:PMC3030971

[20] Gaillard H,Aguilera A.Replication stress and cancer..Nat Rev Cancer2015;15:276-89

[21] Zhang J.Mechanism and regulation of incisions during DNA interstrand cross-link repair..DNA Repair2014;19:135-42 PMCID:PMC4076290

[22] Shaheen R,Ansari S.Genomic analysis of primordial dwarfism reveals novel disease genes..Genome Res2014;24:291-9 PMCID:PMC3912419

[23] Croteau DL,Opresko PL.Human RecQ helicases in DNA repair, recombination, and replication..Annu Rev Biochem2014;83:519-52 PMCID:PMC4586249

[24] Casper AM,Arlt MF.Chromosomal instability at common fragile sites in Seckel syndrome..Am J Hum Genet2004;75:654-60 PMCID:PMC1182052

[25] Gavande NS,Hinshaw HD.DNA repair targeted therapy: The past or future of cancer treatment?.Pharmacol Ther2016;160:65-83 PMCID:PMC4811676

[26] Pearl LH,Ward SE,Pearl FM.Therapeutic opportunities within the DNA damage response..Nat Rev Cancer2015;15:166-80

[27] Nickoloff JA.Paths from DNA damage and signaling to genome rearrangements via homologous recombination..Mutat Res2017;806:64-74

[28] Nickoloff JA,Allen CP.Translational research in radiation-induced DNA damage signaling and repair..Transl Cancer Res2017;6:S875-S91 PMCID:PMC6298755

[29] Desai A,Gerson SL.Advances in therapeutic targeting of the DNA damage response in cancer..DNA Repair2018;66-67:24-9 PMCID:PMC6005187

[30] Blackford AN.ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response..Mol Cell2017;66:801-17

[31] Hengel SR,Spies M.Small-molecule inhibitors targeting DNA repair and DNA repair deficiency in research and cancer therapy..Cell Chem Biol2017;24:1101-19 PMCID:PMC5679738

[32] Killock D.Targeted therapies: DNA polymerase theta-a new target for synthetic lethality?.Nat Rev Clin Oncol2015;12:125

[33] Pilie PG,Mills GB.State-of-the-art strategies for targeting the DNA damage response in cancer..Nat Rev Clin Oncol2019;16:81-104

[34] Carrassa L.DNA damage response inhibitors: Mechanisms and potential applications in cancer therapy..Cancer Treat Rev2017;60:139-51

[35] Nickoloff JA,Lee S-H,Hromas R.Drugging the cancers addicted to DNA repair..J Natl Cancer Inst2017;109:djx059 PMCID:PMC5436301

[36] Yazinski SA.Functions, regulation, and therapeutic implications of the ATR checkpoint pathway..Annu Rev Genet2016;50:155-73

[37] Serrano MA,Dangeti M.DNA-PK, ATM and ATR collaboratively regulate p53-RPA interaction to facilitate homologous recombination DNA repair..Oncogene2013;32:2452-62 PMCID:PMC3651755

[38] Awasthi P,Kumar A.ATM and ATR signaling at a glance..J Cell Sci2015;128:4255-62

[39] Weber AM.ATM and ATR as therapeutic targets in cancer..Pharmacol Ther2015;149:124-38

[40] Williams RM,Zhang X.Structures and regulations of ATM and ATR, master kinases in genome integrity..Curr Opin Struct Biol2020;61:98-105

[41] Mordes DA.Activation of ATR and related PIKKs..Cell Cycle2008;7:2809-12 PMCID:PMC2672405

[42] Matsuoka S,Smogorzewska A.ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage..Science2007;316:1160-6

[43] Tapia-Alveal C,O’Connell MJ.Regulation of Chk1..Cell Div2009;4:8 PMCID:PMC2685127

[44] Merry C,Wang J,Zhang Y.Targeting the checkpoint kinase Chk1 in cancer therapy..Cell Cycle2010;9:279-83 PMCID:PMC3048588

[45] Smith J,Xu N.The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer..Adv Cancer Res2010;108:73-112

[46] Mladenov E,Soni A.DNA double-strand-break repair in higher eukaryotes and its role in genomic instability and cancer: Cell cycle and proliferation-dependent regulation..Semin Cancer Biol2016;37-38:51-64

[47] Berti M.Replication stress: getting back on track..Nat Struct Mol Biol2016;23:103-9 PMCID:PMC5125612

[48] Branzei D.The checkpoint response to replication stress..DNA Repair2009;8:1038-46

[49] Mazouzi A,Loizou JI.DNA replication stress: causes, resolution and disease..Exp Cell Res2014;329:85-93

[50] Zeman MK.Causes and consequences of replication stress..Nat Cell Biol2014;16:2-9 PMCID:PMC4354890

[51] Chang HHY,Adachi N.Non-homologous DNA end joining and alternative pathways to double-strand break repair..Nat Rev Mol Cell Biol2017;18:495-506 PMCID:PMC7062608

[52] Wright WD,Heyer WD.Homologous recombination and the repair of DNA double-strand breaks..J Biol Chem2018;293:10524-35 PMCID:PMC6036207

[53] de Koning AP,Castoe TA,Pollock DD.Repetitive elements may comprise over two-thirds of the human genome..PLoS Genet2011;7:e1002384 PMCID:PMC3228813

[54] Piazza A.Homologous recombination and the formation of complex genomic rearrangements..Trends Cell Biol2019;29:135-49 PMCID:PMC6402879

[55] Guirouilh-Barbat J,Bertrand P.Is homologous recombination really an error-free process?.Front Genet2014;5:175 PMCID:PMC4052342

[56] Sfeir A.Microhomology-mediated end joining: a back-up survival mechanism or dedicated pathway?.Trends Biochem Sci2015;40:701-14 PMCID:PMC4638128

[57] Costantino L,Rantala JK.Break-induced replication repair of damaged forks induces genomic duplications in human cells..Science2014;343:88-91 PMCID:PMC4047655

[58] Iliakis G,Soni A.Alternative end-joining repair pathways are the ultimate backup for abrogated classical non-homologous end-joining and homologous recombination repair: Implications for the formation of chromosome translocations..Mutat Res Genet Toxicol Environ Mutagen2015;793:166-75

[59] Malkova A.Break-induced replication: functions and molecular mechanism..Curr Opin Genet Dev2013;23:271-9 PMCID:PMC3915057

[60] Sotiriou SK,Lugli N.Mammalian RAD52 functions in break-induced replication repair of collapsed DNA replication forks..Mol Cell2016;64:1127-34 PMCID:PMC5179496

[61] Tutt A,Valentine J.Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences..EMBO J2001;20:4704-16 PMCID:PMC125603

[62] Bhargava R,Stark JM.Regulation of single-strand annealing and its role in genome maintenance..Trends Genet2016;32:566-75 PMCID:PMC4992407

[63] Karger CP.RBE and related modeling in carbon-ion therapy..Phys Med Biol2017;63:01TR02

[64] Nickoloff JA,Taylor L.Clustered DNA double-strand breaks: biological effects and relevance to cancer radiotherapy..Genes2020;11:99-116 PMCID:PMC7017136

[65] Paganetti H.Relative biological effectiveness (RBE) values for proton beam therapy. Variations as a function of biological endpoint, dose, and linear energy transfer..Phys Med Biol2014;59:R419-72

[66] Howard M,Sarkaria J.Characterization of relative biological effectiveness for conventional radiation therapy: a comparison of clinical 6 MV X-rays and 137Cs..J Radiat Res2017;58:608-13 PMCID:PMC5737853

[67] Asaithamby A.Cellular responses to DNA double-strand breaks after low-dose γ-irradiation..Nucleic Acids Res2009;37:3912-23 PMCID:PMC2709554

[68] Lomax ME,O’Neill P.Biological consequences of radiation-induced DNA damage: relevance to radiotherapy..Clin Oncol (R Coll Radiol)2013;25:578-85

[69] Vitti ET.The radiobiological effects of proton beam therapy: impact on DNA damage and repair..Cancers2019;11:946 PMCID:PMC6679138

[70] Nickoloff JA.Photon, light ion, and heavy ion cancer radiotherapy: paths from physics and biology to clinical practice..Ann Transl Med2015;3:336 PMCID:PMC4691008

[71] Bukowska B.The clustered DNA lesions - types, pathways of repair and relevance to human health..Curr Med Chem2018;25:2722-35

[72] Mladenova V,Iliakis G.Novel biological approaches for testing the contributions of single DSBs and DSB clusters to the biological effects of high LET radiation..Front Oncol2016;6:163 PMCID:PMC4923065

[73] Sage E.Radiation-induced clustered DNA lesions: Repair and mutagenesis..Free Radic Biol Med2017;107:125-35

[74] Pang D,Jung M.Radiation-generated short DNA fragments may perturb non-homologous end-joining and induce genomic instability..J Radiat Res2011;52:309-19 PMCID:PMC5469405

[75] Chan DW,Prithivirasingh S.Autophosphorylation of the DNA-dependent protein kinase catalytic subunit is required for rejoining of DNA double-strand breaks..Genes Dev2002;16:2333-8 PMCID:PMC187438

[76] Okayasu R,Okabe A.Repair of DNA damage induced by accelerated heavy ions in mammalian cells proficient and deficient in the non-homologous end-joining pathway..Radiat Res2006;165:59-67

[77] Wang H,Wang P.Characteristics of DNA-binding proteins determine the biological sensitivity to high-linear energy transfer radiation..Nucleic Acids Res2010;38:3245-51 PMCID:PMC2879532

[78] Hada M.Spectrum of complex DNA damages depends on the incident radiation..Radiat Res2006;165:223-30

[79] Gerelchuluun A,Ishikawa T.The major DNA repair pathway after both proton and carbon-ion radiation is NHEJ, but the HR pathway is more relevant in carbon ions..Radiat Res2015;183:345-56 PMCID:PMC5684887

[80] Fontana AO,Grosse N.Differential DNA repair pathway choice in cancer cells after proton- and photon-irradiation..Radiother Oncol2015;116:374-80

[81] Vitti ET,Parsons JL.Targeting DNA double-strand break repair enhances radiosensitivity of HPV-positive and HPV-negative head and neck squamous cell carcinoma to photons and protons..Cancers2020;12:1490 PMCID:PMC7352833

[82] Cartwright IM,Haskins JS.DNA repair deficient chinese hamster ovary cells exhibiting differential sensitivity to charged particle radiation under aerobic and hypoxic conditions..Int J Mol Sci2018;19:2228 PMCID:PMC6121575

[83] Antonovic L,Dasu A.Clinical oxygen enhancement ratio of tumors in carbon ion radiotherapy: the influence of local oxygenation changes..J Radiat Res2014;55:902-11 PMCID:PMC4240637

[84] Pawlik TM.Role of cell cycle in mediating sensitivity to radiotherapy..Int J Radiat Oncol Biol Phys2004;59:928-42

[85] Higgins PD,Gould MN.Effect of pulsed dose in simultaneous and sequential irradiation of V-79 cells by 14.8-MeV neutrons and ⁶⁰Co photons..Radiat Res1984;99:591-5

[86] Cheng L,Sollazzo A.Simultaneous induction of dispersed and clustered DNA lesions compromises DNA damage response in human peripheral blood lymphocytes..PLoS One2018;13:e0204068 PMCID:PMC6209146

[87] Staaf E,Haghdoost S,Wojcik A.Gamma-H2AX foci in cells exposed to a mixed beam of X-rays and alpha particles..Genome Integr2012;3:8 PMCID:PMC3531250

[88] Newhauser WD.Assessing the risk of second malignancies after modern radiotherapy..Nat Rev Cancer2011;11:438-48 PMCID:PMC4101897

[89] Tsujii H,Shirai T.Carbon-Ion Radiotherapy Principals, Practices, and Treatment Planning.2014;TokyoSpringer312

[90] Tsujii H.A review of update clinical results of carbon ion radiotherapy..Jpn J Clin Oncol2012;42:670-85 PMCID:PMC3405871

[91] Kamada T,Blakely EA.Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience..Lancet Oncol2015;16:e93-e100

[92] Allen CP,Tsujii H.Heavy charged particle radiobiology: using enhanced biological effectiveness and improved beam focusing to advance cancer therapy..Mutat Res2011;711:150-7 PMCID:PMC3101308

[93] Sunada S,Hirakawa H.Investigation of the relative biological effectiveness and uniform isobiological killing effects of irradiation with a clinical carbon SOBP beam on DNA repair deficient CHO cells..Oncol Lett2017;13:4911-6 PMCID:PMC5453035

[94] Buglewicz DJ,Hirakawa H,Kato TA.Monoenergetic 290 MeV/n carbon-ion beam biological lethal dose distribution surrounding the Bragg peak..Sci Rep2019;9:6157 PMCID:PMC6467899

[95] Kato TA,Nagasaw H.Variations in radiosensitivity among individuals: a potential impact on risk assessment?.Health Phys2009;97:470-80

[96] Wilson PF,Fitzek MM,Bedford JS.G2-phase chromosomal radiosensitivity of primary fibroblasts from hereditary retinoblastoma family members and some apparently normal controls..Radiat Res2010;173:62-70 PMCID:PMC2819004

[97] Kirsch DG.Current opportunities and future vision of precision medicine in radiation oncology..Int J Radiat Oncol Biol Phys2018;101:267-70 PMCID:PMC6499377

[98] Speers C,Liu M.Development and validation of a novel radiosensitivity signature in human breast cancer..Clin Cancer Res2015;21:3667-77

[99] Willers H,Santivasi WL.Basic mechanisms of therapeutic resistance to radiation and chemotherapy in lung cancer..Cancer J2013;19:200-7 PMCID:PMC3668666

[100] Hill RP,Fyles A.Hypoxia and predicting radiation response..Semin Radiat Oncol2015;25:260-72

[101] Kim BM,Lee S.Therapeutic implications for overcoming radiation resistance in cancer therapy..Int J Mol Sci2015;16:26880-913 PMCID:PMC4661850

[102] Hu J,Luo X.The role of oxidative stress in EBV lytic reactivation, radioresistance and the potential preventive and therapeutic implications..Int J Cancer2017;141:1722-9

[103] Wardman P.Nitroimidazoles as hypoxic cell radiosensitizers and hypoxia probes: misonidazole, myths and mistakes..Br J Radiol2019;92:20170915 PMCID:PMC6435051

[104] Bonnet M,Wong WW.Next-generation hypoxic cell radiosensitizers: nitroimidazole alkylsulfonamides..J Med Chem2018;61:1241-54

[105] Olivares-Urbano MA,Marchal JA.CSC radioresistance: a therapeutic challenge to improve radiotherapy effectiveness in cancer..Cells2020;9:1651 PMCID:PMC7407195

[106] Liu Y,Luo J.Radiotherapy targeting cancer stem cells “awakens” them to induce tumour relapse and metastasis in oral cancer..Int J Oral Sci2020;12:19 PMCID:PMC7311531

[107] Schulz A,Dubrovska A.Cancer stem cells and radioresistance: DNA repair and beyond..Cancers2019;11:862 PMCID:PMC6627210

[108] Talukdar S,Emdad L.Dormancy and cancer stem cells: An enigma for cancer therapeutic targeting..Adv Cancer Res2019;141:43-84

[109] Peeken JC,Combs SE.Integrating hyperthermia into modern radiation oncology: What evidence Is necessary?.Front Oncol2017;7:132 PMCID:PMC5492395

[110] Oei AL,Crezee J,Krawczyk PM.Effects of hyperthermia on DNA repair pathways: one treatment to inhibit them all..Radiat Oncol2015;10:165 PMCID:PMC4554295

[111] Genet SC,Maeda J.Hyperthermia inhibits homologous recombination repair and sensitizes cells to ionizing radiation in a time- and temperature-dependent manner..J Cell Physiol2013;228:1473-81

[112] Zhu L,Laszlo A.Ultrasound hyperthermia technology for radiosensitization..Ultrasound Med Biol2019;45:1025-43 PMCID:PMC6475527

[113] Lewis JE,Holmila RJ.Targeting NAD⁺ Metabolism to Enhance Radiation Therapy Responses..Semin Radiat Oncol2019;29:6-15 PMCID:PMC6310039

[114] Ashcraft KA,Jones LW.Exercise as adjunct therapy in cancer..Semin Radiat Oncol2019;29:16-24 PMCID:PMC6656408

[115] Schoenfeld JD,Waldron TJ.Pharmacological ascorbate as a means of sensitizing cancer cells to radio-chemotherapy while protecting normal tissue..Semin Radiat Oncol2019;29:25-32 PMCID:PMC6310038

[116] Floberg JM.Manipulation of glucose and hydroperoxide metabolism to improve radiation response..Semin Radiat Oncol2019;29:33-41 PMCID:PMC6310057

[117] Aykin-Burns N,Boerma M,Hauer-Jensen M.Utilization of vitamin E analogs to protect normal tissues while enhancing antitumor effects..Semin Radiat Oncol2019;29:55-61 PMCID:PMC6309800

[118] Hillman GG.Soy isoflavones protect normal tissues while enhancing radiation responses..Semin Radiat Oncol2019;29:62-71

[119] Boss MK,Batinic-Haberle I.Manganese porphyrin and radiotherapy improves local tumor response and overall survival in orthotopic murine mammary carcinoma models..Radiat Res2020;(in press)

[120] Mortezaee K,Musa AE,Farhood B.Metformin as a radiation modifier; implications to normal tissue protection and tumor sensitization..Curr Clin Pharmacol2019;14:41-53

[121] Lin A.Molecular pathways: A novel approach to targeting hypoxia and improving radiotherapy efficacy via reduction in oxygen demand..Clin Cancer Res2015;21:1995-2000 PMCID:PMC4418024

[122] Fernandes JM,Koyama FC.Metformin as an alternative radiosensitizing agent to 5FU during neoadjuvant treatment for rectal cancer..Dis Colon Rectum2020;63:918-26

[123] Farhood B,Mortezaee K.Melatonin as an adjuvant in radiotherapy for radioprotection and radiosensitization..Clin Transl Oncol2019;21:268-79

[124] Citrin DE.Radiation modifiers..Hematol Oncol Clin North Am2019;33:1041-55

[125] Livingston K,Puckett LL.The role of mitochondrial dysfunction in radiation-induced heart disease: from bench to bedside..Front Cardiovasc Med2020;7:20 PMCID:PMC7047199

[126] Thermozier S,Zhang X.Anti-ferroptosis drug enhances total-body irradiation mitigation by drugs that block apoptosis and necroptosis..Radiat Res2020;193:435-50 PMCID:PMC7299160

[127] Olivieri G,Wolff S.Adaptive response of human lymphocytes to low concentrations of radioactive thymidine..Science1984;223:594-7

[128] Huang L,Nickoloff JA.Targeted and non-targeted effects of low-dose ionizing radiation on delayed genomic instability in human cells..Cancer Res2007;67:1099-104

[129] Ikushima T.Radio-adaptive response: characterization of a cytogenetic repair induced by low-level ionizing radiation in cultured Chinese hamster cells..Mutat Res1989;227:241-6

[130] Rigaud O.Radioadaptation for gene mutation and the possible molecular mechanisms of the adaptive response..Mutat Res1996;358:127-34

[131] Redpath JL.Induction of an adaptive response against spontaneous neoplastic transformation in vitro by low-dose gamma radiation..Radiat Res1998;149:517-20

[132] Barquinero JF,Caballin MR.Occupational exposure to radiation induces an adaptive response in human lymphocytes..Int J Radiat Biol1995;67:187-91

[133] Monsieurs MA,Vral AM.Adaptive response in patients treated with ¹³¹I..J Nucl Med2000;41:17-22

[134] Grdina DJ,Miller RC.A survivin-associated adaptive response in radiation therapy..Cancer Res2013;73:4418-28 PMCID:PMC3721325

[135] Grdina DJ,Miller RC.A manganese superoxide dismutase (SOD2)-mediated adaptive response..Radiat Res2013;179:115-24 PMCID:PMC3594688

[136] Grdina DJ,Miller RC,Li JJ.NFkappaB and survivin-mediated radio-adaptive response..Radiat Res2015;183:391-7

[137] Murley JS,Weichselbaum RR.TP53 mutational status and ROS effect the expression of the survivin-associated radio-adaptive response..Radiat Res2017;188:579-90 PMCID:PMC5705057

[138] Murley JS,Weichselbaum RR.ROS modifiers and NOX4 affect the expression of the survivin-associated radio-adaptive response..Free Radic Biol Med2018;123:39-52

[139] Unruhe B,Wunsch D.An old flame never dies: Survivin in cancer and cellular senescence..Gerontology2016;62:173-81

[140] Coleman CN,Makinde AY.Radiation-induced adaptive response: new potential for cancer treatment..Clin Cancer Res2020;26:5781-90 PMCID:PMC7669567

[141] Sato H,Yasuhara T.DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells..Nat Commun2017;8:1751 PMCID:PMC5701012

[142] Gerlinger M.Targeted drugs ramp up cancer mutability..Science2019;366:1452-3

[143] Russo M,Sogari A.Adaptive mutability of colorectal cancers in response to targeted therapies..Science2019;366:1473-80

[144] Scott JG,Schell MJ.A genome-based model for adjusting radiotherapy dose (GARD): a retrospective, cohort-based study..Lancet Oncol2017;18:202-11

[145] Trenner A.Harnessing DNA double-strand break repair for cancer treatment..Front Oncol2019;9:1388 PMCID:PMC6921965

[146] Kirsch DG,Kesarwala AH.The future of radiobiology..J Natl Cancer Inst2018;110:329-40 PMCID:PMC5928778

[147] Kelley MR,Fishel ML.Targeting DNA repair pathways for cancer treatment: what’s new?.Future Oncol2014;10:1215-37 PMCID:PMC4125008

[148] Toulany M.Targeting DNA double-strand break repair pathways to improve radiotherapy response..Genes2019;10:25 PMCID:PMC6356315

[149] Mohiuddin IS.DNA-PK as an emerging therapeutic target in cancer..Front Oncol2019;9:635 PMCID:PMC6650781

[150] Dong J,Zhang T.Inactivation of DNA-PK by knockdown DNA-PKcs or NU7441 impairs non-homologous end-joining of radiation-induced double strand break repair..Oncol Rep2018;39:912-20 PMCID:PMC5802037

[151] Yang C,Liu X.NU7441 enhances the radiosensitivity of liver cancer cells..Cell Physiol Biochem2016;38:1897-905

[152] Sunada S,Lee Y.Nontoxic concentration of DNA-PK inhibitor NU7441 radio-sensitizes lung tumor cells with little effect on double strand break repair..Cancer Sci2016;107:1250-5 PMCID:PMC5021029

[153] Timme CR,O’Neill JW,Tofilon PJ.The DNA-PK inhibitor VX-984 enhances the radiosensitivity of glioblastoma cells grown in vitro and as orthotopic xenografts..Mol Cancer Ther2018;17:1207-16 PMCID:PMC6322200

[154] Willoughby CE,Thomas HD.Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy..J Clin Invest2020;130:258-71 PMCID:PMC6934184

[155] Smith MC,Cook JA.Characterization of LY3023414, a vovel PI3K/mTOR dual inhibitor eliciting transient target modulation to impede tumor growth..Mol Cancer Ther2016;15:2344-56

[156] Tsuji T,Tran T.CC-115, a dual inhibitor of mTOR kinase and DNA-PK, blocks DNA damage repair pathways and selectively inhibits ATM-deficient cell growth in vitro..Oncotarget2017;8:74688-702 PMCID:PMC5650372

[157] Lindquist KE,Kordic K.Selective radiosensitization of hypoxic cells using BCCA621C: a novel hypoxia activated prodrug targeting DNA-dependent protein kinase..Tumour Microenv Ther2013;1:46-55

[158] Dittmann K,Rodemann HP.Inhibition of radiation-induced EGFR nuclear import by C225 (Cetuximab) suppresses DNA-PK activity..Radiother Oncol2005;76:157-61

[159] Joseph K,Warkentin H.Cetuximab-radiotherapy combination in the management of locally advanced cutaneous squamous cell carcinoma..J Med Imaging Radiat Oncol2019;63:257-63

[160] Qi Y,Zhu X.Down-regulation of the radiation-induced pEGFRThr654 mediated activation of DNA-PK by Cetuximab in cervical cancer cells.RSC Adv2020;10:1132-41

[161] Balbous A,Guilloteau K.A radiosensitizing effect of RAD51 inhibition in glioblastoma stem-like cells..BMC Cancer2016;16:604 PMCID:PMC4974671

[162] King HO,Payne HL.RAD51 Is a selective DNA repair target to radiosensitize glioma stem cells..Stem Cell Reports2017;8:125-39 PMCID:PMC5233453

[163] Pastushok L,Lin L.A novel cell-penetrating antibody fragment inhibits the DNA repair protein RAD51..Sci Rep2019;9:11227 PMCID:PMC6677837

[164] Turchick A,Zhao W,Glazer PM.Synthetic lethality of a cell-penetrating anti-RAD51 antibody in PTEN-deficient melanoma and glioma cells..Oncotarget2019;10:1272-83 PMCID:PMC6407680

[165] Turchick A,Jensen RB.A cell-penetrating antibody inhibits human RAD51 via direct binding..Nucleic Acids Res2017;45:11782-99 PMCID:PMC5714174

[166] Cyteir Therapeutics IA phase 1/2 study of CYT-0851, an oral RAD51 inhibitor, in B-cell malignancies and advanced solid tumors. In;2019;

[167] Yu D,Fujimori A,Okayasu R.Down regulation of BRCA2 causes radio-sensitization of human tumor cells in vitro and in vivo..Cancer Sci2008;99:810-5

[168] Hirai T,Fujimori H.Radiosensitization effect of poly(ADP-ribose) polymerase inhibition in cells exposed to low and high linear energy transfer radiation..Cancer Sci2012;103:1045-50 PMCID:PMC7685087

[169] Hirai T,Fujimori H.Radiosensitization by PARP inhibition to proton beam irradiation in cancer cells..Biochem Biophys Res Commun2016;478:234-40

[170] Jannetti SA,Zalutsky MR.Poly(ADP-ribose)polymerase (PARP) inhibitors and radiation therapy..Front Pharmacol2020;11:170 PMCID:PMC7062869

[171] Chang L,Hao J.PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways..Cell Death Dis2014;5:e1437 PMCID:PMC4237243

[172] Schotz U,Brandt FW.Dual PI3K/mTOR inhibitor NVP-BEZ235 enhances radiosensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines due to suppressed double-strand break (DSB) repair by non-homologous end joining..Cancers2020;12:467 PMCID:PMC7072694

[173] Gil del Alcazar CR,Mukherjee B.Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma..Clin Cancer Res2014;20:1235-48 PMCID:PMC3947495

[174] Hirakawa H,Masaoka A.The combination of Hsp90 inhibitor 17AAG and heavy-ion irradiation provides effective tumor control in human lung cancer cells..Cancer Med2015;4:426-36 PMCID:PMC4380968

[175] Lee Y,Masaoka A.The purine scaffold Hsp90 inhibitor PU-H71 sensitizes cancer cells to heavy ion radiation by inhibiting DNA repair by homologous recombination and non-homologous end joining..Radiother Oncol2016;121:162-8 PMCID:PMC5110220

[176] Noguchi M,Hirayama R.Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin..Biochem Biophys Res Commun2006;351:658-63

[177] Segawa T,Tanaka A.Radiosensitization of human lung cancer cells by the novel purine-scaffold Hsp90 inhibitor, PU-H71..Int J Mol Med2014;33:559-64

[178] Lee Y,Hirakawa H.TAS-116, a novel Hsp90 inhibitor, selectively enhances radiosensitivity of human cancer cells to X-rays and carbon ion radiation..Mol Cancer Ther2017;16:16-24 PMCID:PMC5221699

[179] Fujii Y,Kubota N.p53 independent radio-sensitization of human lymphoblastoid cell lines by Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin..Oncol Rep2010;23:199-203

[180] Shimomura A,Kondo S.First-in-human Phase I study of an oral HSP90 inhibitor, TAS-116, in patients with advanced solid tumors..Mol Cancer Ther2019;18:531-40

[181] Vormoor B,Blair H.Sensitizing Ewing sarcoma to chemo- and radiotherapy by inhibition of the DNA-repair enzymes DNA protein kinase (DNA-PK) and poly-ADP-ribose polymerase (PARP) 1/2..Oncotarget2017;8:113418-30 PMCID:PMC5768336

[182] Fok JHL,Vazquez-Chantada M.AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity..Nat Commun2019;10:5065 PMCID:PMC6838110

[183] Zhang Q,Lang X.Inhibition of ATM increases interferon signaling and sensitizes pancreatic cancer to immune checkpoint blockade therapy..Cancer Res2019;79:3940-51 PMCID:PMC6684166

[184] Chen BP,Kobayashi J.Ataxia telangiectasia mutated (ATM) is essential for DNA-PKcs phosphorylations at the Thr-2609 cluster upon DNA double strand break..J Biol Chem2007;282:6582-7

[185] Cornell L,Alsinet C.DNA-PK-A candidate driver of hepatocarcinogenesis and tissue biomarker that predicts response to treatment and survival..Clin Cancer Res2015;21:925-33 PMCID:PMC4335075

[186] Abdel-Fatah TM,Moseley P.ATM, ATR and DNA-PKcs expressions correlate to adverse clinical outcomes in epithelial ovarian cancers..BBA Clin2014;2:10-7 PMCID:PMC4633921

[187] Toulany M,Iida M.Akt1 and Akt3 but not Akt2 through interaction with DNA-PKcs stimulate proliferation and post-irradiation cell survival of K-RAS-mutated cancer cells..Cell Death Discov2017;3:17072 PMCID:PMC5661268

[188] Baptistella AR,Dias MVS.Rab5C enhances resistance to ionizing radiation in rectal cancer..J Mol Med2019;97:855-69

[189] Zou M,Xia S.Knockdown of CAVEOLIN-1 sensitizes human basal-like triple-negative breast cancer cells to radiation..Cell Physiol Biochem2017;44:778-91

[190] Saki M,Javvadi P.EGFR mutations compromise hypoxia-associated radiation resistance through impaired replication fork-associated DNA damage repair..Mol Cancer Res2017;15:1503-16 PMCID:PMC5668182

[191] Amunugama R.Homologous recombination in eukaryotes..Prog Mol Biol Transl Sci2012;110:155-206

[192] Shrivastav M,De Haro LP.DNA-PKcs and ATM co-regulate DNA double-strand break repair..DNA Repair2009;8:920-9 PMCID:PMC3071034

[193] Nickoloff JA.Analysis of recombinational repair of DNA double-strand breaks in mammalian cells with I-SceI nuclease..Methods Mol Biol2004;262:35-52

[194] Yoshino Y,Chen Z.Evaluation of site-specific homologous recombination activity of BRCA1 by direct quantitation of gene editing efficiency..Sci Rep2019;9:1644 PMCID:PMC6367331

[195] Price BD.Chromatin remodeling at DNA double-strand breaks..Cell2013;152:1344-54 PMCID:PMC3670600

[196] Kaushal S.The role of fork stalling and DNA structures in causing chromosome fragility..Genes Chromosomes Cancer2019;58:270-83 PMCID:PMC7083089

[197] Wray J,Nickoloff JA.Distinct RAD51 associations with RAD52 and BCCIP in response to DNA damage and replication stress..Cancer Res2008;68:2699-707 PMCID:PMC2744103

[198] Groth P,Elvers I.Homologous recombination repairs secondary replication induced DNA double-strand breaks after ionizing radiation..Nucleic Acids Res2012;40:6585-94 PMCID:PMC3413124

[199] Murnane JP.Telomere dysfunction and chromosome instability..Mutat Res2012;730:28-36 PMCID:PMC3178001

[200] Budke B,Kalin JH.RI-1: a chemical inhibitor of RAD51 that disrupts homologous recombination in human cells..Nucleic Acids Res2012;40:7347-57 PMCID:PMC3424541

[201] Budke B,Kozikowski AP.Recent developments using small molecules to target RAD51: How to best modulate RAD51 for anticancer therapy?.ChemMedChem2016;11:2468-73 PMCID:PMC5472043

[202] Lv W,Pawlowski M,Kozikowski AP.Development of small molecules that specifically inhibit the D-loop activity of RAD51..J Med Chem2016;59:4511-25 PMCID:PMC5473336

[203] Mersch J,Park M.Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian..Cancer2015;121:269-75 PMCID:PMC4293332

[204] Sekhar D,Kumar S.RAD51 135G > C substitution increases breast cancer risk in an ethnic-specific manner: a meta-analysis on 21,236 cases and 19,407 controls..Sci Rep2015;5:11588 PMCID:PMC4479800

[205] Evans MK.PALB2 mutations and breast-cancer risk..N Engl J Med2014;371:566-8 PMCID:PMC4669041

[206] Jette NR,Radhamani S.ATM-deficient cancers provide new opportunities for precision oncology..Cancers2020;12:687 PMCID:PMC7140103

[207] Byrum AK,Mosammaparast N.Defining and modulating ‘BRCAness’..Trends Cell Biol2019;29:740-51

[208] Pommier Y,de Bono J.Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action..Sci Transl Med2016;8:362ps17

[209] Yi M,Qin S.Advances and perspectives of PARP inhibitors..Exp Hematol Oncol2019;8:29 PMCID:PMC6849303

[210] del Rivero J.PARP inhibitors: the cornerstone of DNA repair-targeted therapies..Oncology2017;31:265-73

[211] Gil Del Alcazar CR,Habib AA,Burma S.Augmented HR repair mediates acquired temozolomide resistance in glioblastoma..Mol Cancer Res2016;14:928-40 PMCID:PMC5065752

[212] Zhang X,Yao W,Ren Z.RAD51 is a potential marker for prognosis and regulates cell proliferation in pancreatic cancer..Cancer Cell Int2019;19:356 PMCID:PMC6935217

[213] Liu X,Anderson M.Acquired resistance to combination treatment with temozolomide and ABT-888 is mediated by both base excision repair and homologous recombination DNA repair pathways..Mol Cancer Res2009;7:1686-92

[214] Noordermeer SM.PARP inhibitor resistance: a tug-of-war in BRCA-mutated cells..Trends Cell Biol2019;29:820-34

[215] D’Andrea AD.Mechanisms of PARP inhibitor sensitivity and resistance..DNA Repair2018;71:172-6

[216] Tian H,Li H.DNA damage response--a double-edged sword in cancer prevention and cancer therapy..Cancer Lett2015;358:8-16

[217] Bakr A,Kocher S.Involvement of ATM in homologous recombination after end resection and RAD51 nucleofilament formation..Nucleic Acids Res2015;43:3154-66 PMCID:PMC4381069

[218] Ahlskog JK,Achanta K.ATM/ATR-mediated phosphorylation of PALB2 promotes RAD51 function..EMBO Rep2016;17:671-81 PMCID:PMC5341514

[219] Jackson SP.Drugging DNA repair..Science2016;352:1178-9 PMCID:PMC5940588

[220] Glorieux M,Nuyts S.Novel DNA targeted therapies for head and neck cancers: clinical potential and biomarkers..Oncotarget2017;8:81662-78 PMCID:PMC5655317

[221] Riches LC,Hughes G.Pharmacology of the ATM inhibitor AZD0156: potentiation of irradiation and olaparib responses preclinically..Mol Cancer Ther2020;19:13-25

[222] Zhou C.The radiobiology of HPV-positive and HPV-negative head and neck squamous cell carcinoma..Expert Rev Mol Med2020;22:e3

[223] Ferri A,Barila D.Targeting the DNA damage response to overcome cancer drug resistance in glioblastoma..Int J Mol Sci2020;21:4910 PMCID:PMC7402284

[224] Philip CA,Beauchamp MC.Inhibition of PI3K-AKT-mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors..BMC Cancer2017;17:638 PMCID:PMC5591502

[225] Wang D,Zhang Y.Combined inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes..Gynecol Oncol2016;142:548-56 PMCID:PMC5551048

[226] Cossar LH,Risk JM.Modulating the DNA damage response to improve treatment response in cervical cancer..Clin Oncol2017;29:626-34

[227] Weitzman MD.Virus DNA replication and the host DNA damage response..Annu Rev Virol2018;5:141-64 PMCID:PMC6462412

[228] Jafari A,Farhadihosseinabadi B,Zali H.HSP90 and co-chaperones: impact on tumor progression and prospects for molecular-targeted cancer therapy..Cancer Invest2020;38:310-28

[229] Garcia-Carbonero R,Paz-Ares L.Inhibition of HSP90 molecular chaperones: moving into the clinic..Lancet Oncol2013;14:e358-69

[230] Jhaveri K.HSP90 inhibitors for cancer therapy and overcoming drug resistance..Adv Pharmacol2012;65:471-517

[231] Kamal A,Sensintaffar J.A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors..Nature2003;425:407-10

[232] Moulick K,Zong H.Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90..Nat Chem Biol2011;7:818-26 PMCID:PMC3265389

[233] Sessa C,Bhalla KN.First-in-human phase I dose-escalation study of the HSP90 inhibitor AUY922 in patients with advanced solid tumors..Clin Cancer Res2013;19:3671-80

[234] Renouf DJ,Simpson R,Bedard PL.Ocular toxicity of targeted therapies..J Clin Oncol2012;30:3277-86

[235] Balmus G,Coates J.ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks..Nat Commun2019;10:87 PMCID:PMC6325118

[236] Nickoloff JA.Improving cancer therapy by combining cell biological, physical, and molecular targeting strategies..Chin J Cancer Res2013;25:7-9 PMCID:PMC3555295

[237] Kon T,Huang Q.Oncolytic virus-mediated tumor radiosensitization in mice through DNA-PKcs-specific shRNA..Transl Cancer Res2012;1:4-14 PMCID:PMC3426860

[238] Guo P,Jia D,Auguste DT.ICAM-1-targeted, Lcn2 siRNA-encapsulating liposomes are potent anti-angiogenic agents for triple negative breast cancer..Theranostics2016;6:1-13 PMCID:PMC4679350

[239] Guo P,Huang J,Moses MA.Therapeutic genome editing of triple-negative breast tumors using a noncationic and deformable nanolipogel..Proc Natl Acad Sci USA2019;116:18295-303 PMCID:PMC6744870