Radiotherapy and the cellular DNA damage response: current and future perspectives on head and neck cancer treatment

Abstract

Incidences of head and neck squamous cell carcinoma (HNSCC) have been on the rise in the last few decades, with a significant risk factor being human papillomavirus (HPV) type-16/18 infection, particularly in the development of oropharyngeal cancers. Radiotherapy (RT) is an important treatment modality for HNSCC, where it promotes extensive cellular DNA damage leading to the therapeutic effect. It has been well-established that HPV-positive HNSCC display better response rates and improved survival following RT compared to HPV-negative HNSCC. The differential radiosensitivity has been largely associated with altered cellular DNA damage response mechanisms in HPV-positive HNSCC, and particularly with the signaling and repair of DNA double strand breaks. However, other factors, particularly hypoxia present within the solid cancer, have a major impact on relative radioresistance. Consequently, recent approaches aimed at enhancing the radiosensitivity of HNSCC have largely centered on targeting key proteins involved in DNA repair, DNA damage checkpoint activation, and hypoxia signaling. These studies have utilised in vitro and in vivo models of HPV-positive and HPV-negative HNSCC and examined the impact of specific inhibitors against the targets in combination with radiation in suppressing HNSCC cell growth and survival. Here, accumulating evidence has shown that targeting enzymes including poly (ADP-ribose) polymerase, ataxia telangiectasia and Rad-3 related, DNA-dependent protein kinase catalytic subunit, and checkpoint kinase 1 can radiosensitise HNSCC cells which should be taken forward in further preclinical studies, with the goal of optimizing the future effective RT treatment of HNSCC.

Keywords

DNA damage / DNA repair / head and neck cancer / ionising radiation / proton beam therapy / radiobiology / radiotherapy

References

[1] Office for National Statistics. Cancer registration statistics, England: 2017. Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/cancerregistrationstatisticsengland/2017. [Last accessed on 9 Sep 2020]

[2] Public Health Wales. Cancer registration statistics, Wales: 2017. Available from: http://www.wcisu.wales.nhs.uk/cancer-incidence-in-wales. [Last accessed on 9 Sep 2020]

[3] Public Health Scotland. Cancer registration statistics, Scotland: 2017. Available from: https://www.isdscotland.org/Health-Topics/Cancer/Cancer-Statistics/. [Last accessed on 9 Sep 2020]

[4] Northern Ireland Cancer Registry. Cancer registration statistics, Northern Ireland: 2017. Available from: https://www.publichealth.hscni.net/directorate-public-health/service-development-and-screening/northern-ireland-cancer-registry. [Last accessed on 9 Sep 2020]

[5] Kobayashi K,Suzui N,Tomita H.A review of HPV-related head and neck cancer..J Clin Med2018;7: PMCID:PMC6162868

[6] National Cancer Registration & Analysis Service and Cancer Research UK. Chemotherapy, Radiotherapy and Surgical Tumour Resections in England. Availabe from: http://www.ncin.org.uk/cancer_type_and_topic_specific_work/topic_specific_work/main_cancer_treatments. [Last accessed on 9 Sep 2020]

[7] Kim JK,Riaz N,Tsai CJ.Proton therapy for head and neck cancer..Curr Treat Options Oncol2018;19:28

[8] Stanisce L,Xu Q,Squillante C.Stereotactic body radiotherapy treatment for recurrent, previously irradiated head and neck cancer..Technol Cancer Res Treat2018;17:1533033818780086 PMCID:PMC6024262

[9] Castelli J,Lafond C,Rigaud B.Adaptive radiotherapy for head and neck cancer..Acta Oncol2018;57:1284-92

[10] Jackson SP.The DNA-damage response in human biology and disease..Nature2009;461:1071-8 PMCID:PMC2906700

[11] Ranjha L,Cejka P.Main steps in DNA double-strand break repair: an introduction to homologous recombination and related processes..Chromosoma2018;127:187-214

[12] Pannunzio NR,Lieber MR.Nonhomologous DNA end-joining for repair of DNA double-strand breaks..J Biol Chem2018;293:10512-23 PMCID:PMC6036208

[13] Mao Z,Seluanov A.DNA repair by nonhomologous end joining and homologous recombination during cell cycle in human cells..Cell Cycle2008;7:2902-6 PMCID:PMC2754209

[14] Goodhead DT.Energy deposition stochastics and track structure: what about the target?.Radiat Prot Dosimetry2006;122:3-15

[15] Hill MA.Radiation track structure: how the spatial distribution of energy deposition drives biological response..Clin Oncol (R Coll Radiol)2020;32:75-83

[16] Loeffler JS.Charged particle therapy--optimization, challenges and future directions..Nat Rev Clin Oncol2013;10:411-24

[17] 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..Cancers (Basel)2020;12: PMCID:PMC7352833

[18] Carter RJ,Thompson JM,Hill MA.Complex DNA damage induced by high linear energy transfer alpha-particles and protons triggers a specific cellular DNA damage response..Int J Radiat Oncol Biol Phys2018;100:776-84 PMCID:PMC5796827

[19] Carter RJ.Base excision repair, a pathway regulated by posttranslational modifications..Mol Cell Biol2016;36:1426-37 PMCID:PMC4859697

[20] Edmonds MJ.Regulation of base excision repair proteins by ubiquitylation..Exp Cell Res2014;329:132-8

[21] Carter RJ,Thompson JM,Hill MA.Characterisation of deubiquitylating enzymes in the cellular response to high-LET ionizing radiation and complex DNA damage..Int J Radiat Oncol Biol Phys2019;104:656-65 PMCID:PMC6542414

[22] Berman TA.Human papillomavirus in cervical cancer and oropharyngeal cancer: one cause, two diseases..Cancer2017;123:2219-29

[23] Ang KK,Wheeler R,Rosenthal DI.Human papillomavirus and survival of patients with oropharyngeal cancer..N Engl J Med2010;363:24-35 PMCID:PMC2943767

[24] Rieckmann T,Grob TJ,Busch CJ.HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity..Radiother Oncol2013;107:242-6

[25] Nickson CM,Carter RJ,Parsons JL.Misregulation of DNA damage repair pathways in HPV-positive head and neck squamous cell carcinoma contributes to cellular radiosensitivity..Oncotarget2017;8:29963-75 PMCID:PMC5444717

[26] Weaver AN,Rodriguez M,Bonner JA.DNA double strand break repair defect and sensitivity to poly ADP-ribose polymerase (PARP) inhibition in human papillomavirus 16-positive head and neck squamous cell carcinoma..Oncotarget2015;6:26995-7007 PMCID:PMC4694969

[27] Dok R,Glorieux M,Sablina A.Radiosensitization approaches for HPV-positive and HPV-negative head and neck squamous carcinomas..Int J Cancer2020;146:1075-85 PMCID:PMC6973261

[28] Ruttkay-Nedecky B,Nejdl L,Gumulec J.Relevance of infection with human papillomavirus: the role of the p53 tumor suppressor protein and E6/E7 zinc finger proteins (Review)..Int J Oncol2013;43:1754-62

[29] Prigge ES,von Knebel Doeberitz M.Diagnostic accuracy of p16(INK4a) immunohistochemistry in oropharyngeal squamous cell carcinomas: a systematic review and meta-analysis..Int J Cancer2017;140:1186-98

[30] Dok R,Van Limbergen EJ,Vazquez I.p16INK4a impairs homologous recombination-mediated DNA repair in human papillomavirus-positive head and neck tumors..Cancer Res2014;74:1739-51

[31] Wang L,Molkentine DP,Molkentine JM.TRIP12 as a mediator of human papillomavirus/p16-related radiation enhancement effects..Oncogene2017;36:820-8 PMCID:PMC5434711

[32] Gray LH,Ebert M,Scott OC.The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy..Br J Radiol1953;26:638-48

[33] Thomlinson RH.The histological structure of some human lung cancers and the possible implications for radiotherapy..Br J Cancer1955;9:539-49 PMCID:PMC2073776

[34] Evans SM,Chalian AA,Zhang PJ.Patterns and levels of hypoxia in head and neck squamous cell carcinomas and their relationship to patient outcome..Int J Radiat Oncol Biol Phys2007;69:1024-31 PMCID:PMC2737259

[35] Becker A,Bloching M,Lautenschlager C.Oxygenation of squamous cell carcinoma of the head and neck: comparison of primary tumors, neck node metastases, and normal tissue..Int J Radiat Oncol Biol Phys1998;42:35-41

[36] Ivan M,Yang H,Valiando J.HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing..Science2001;292:464-8

[37] Jaakkola P,Tian YM,Gielbert J.Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation..Science2001;292:468-72

[38] Maxwell PH,Chang GW,Vaux EC.The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis..Nature1999;399:271-5

[39] Ke Q.Hypoxia-inducible factor-1 (HIF-1)..Mol Pharmacol2006;70:1469-80

[40] Dengler VL,Espinosa JM.Transcriptional regulation by hypoxia inducible factors..Crit Rev Biochem Mol Biol2014;49:1-15 PMCID:PMC4342852

[41] Knuth J,Wurdemann N,Garvalov BK.Hypoxia-inducible factor-1alpha activation in HPV-positive head and neck squamous cell carcinoma cell lines..Oncotarget2017;8:89681-91 PMCID:PMC5685701

[42] Bencokova Z,Pires IM,Giaccia AJ.ATM activation and signaling under hypoxic conditions..Mol Cell Biol2009;29:526-37 PMCID:PMC2612523

[43] Melvin A.Chromatin as an oxygen sensor and active player in the hypoxia response..Cell Signal2012;24:35-43 PMCID:PMC3476533

[44] Luoto KR,Bristow RG.Tumor hypoxia as a driving force in genetic instability..Genome Integr2013;4:5 PMCID:PMC4016142

[45] Hammond EM,Giaccia AJ.ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to reoxygenation..J Biol Chem2003;278:12207-13

[46] Bristow RG.Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability..Nat Rev Cancer2008;8:180-92

[47] Hammond EM,Dorie MJ,Giaccia AJ.Hypoxia links ATR and p53 through replication arrest..Mol Cell Biol2002;22:1834-43 PMCID:PMC135616

[48] Sorensen BS,Olthof N,Horsman MR.Radiosensitivity and effect of hypoxia in HPV positive head and neck cancer cells..Radiother Oncol2013;108:500-5

[49] Hauth F,Zips D.Cell-line dependent effects of hypoxia prior to irradiation in squamous cell carcinoma lines..Clin Transl Radiat Oncol2017;5:12-9 PMCID:PMC5833923

[50] Gottgens EL,Ansems M,Span PN.AKT inhibition as a strategy for targeting hypoxic HPV-positive HNSCC..Radiother Oncol2020;149:1-7

[51] Nowsheen S,Yang ES.The poly(ADP-Ribose) polymerase inhibitor ABT-888 reduces radiation-induced nuclear EGFR and augments head and neck tumor response to radiotherapy..Radiother Oncol2011;99:331-8 PMCID:PMC3157293

[52] Wurster S,Parplys AC,Mansour WY.PARP1 inhibition radiosensitizes HNSCC cells deficient in homologous recombination by disabling the DNA replication fork elongation response..Oncotarget2016;7:9732-41 PMCID:PMC4891080

[53] Hernandez AL,Bian L,Nolan K.PARP inhibition enhances radiotherapy of SMAD4-deficient human head and neck squamous cell carcinomas in experimental models..Clin Cancer Res2020;26:3058-70 PMCID:PMC7299799

[54] Guster JD,Busch CJ,Petersen C.The inhibition of PARP but not EGFR results in the radiosensitization of HPV/p16-positive HNSCC cell lines..Radiother Oncol2014;113:345-51

[55] Wang L,Wang X,Wang Z.Proton and photon radiosensitization effects of niraparib, a PARP-1/-2 inhibitor, on human head and neck cancer cells..Head Neck2020;42:2244-56

[56] Molkentine JM,Bridges KA,Yang L.Targeting DNA damage response in head and neck cancers through abrogation of cell cycle checkpoints..Int J Radiat Biol2020;1-8 PMCID:PMC7483862

[57] Pires IM,Anbalagan S,Reaper PM.Targeting radiation-resistant hypoxic tumour cells through ATR inhibition..Br J Cancer2012;107:291-9 PMCID:PMC3394988

[58] Dillon MT,Pedersen M,Bhide SA.Radiosensitization by the ATR inhibitor AZD6738 through generation of acentric micronuclei..Mol Cancer Ther2017;16:25-34 PMCID:PMC5302142

[59] Hafsi H,Barker HE,Schick U.Combined ATR and DNA-PK inhibition radiosensitizes tumor cells independently of their p53 status..Front Oncol2018;8:245 PMCID:PMC6053502

[60] Dohmen AJC,Duursma A,Lieftink C.Identification of a novel ATM inhibitor with cancer cell specific radiosensitization activity..Oncotarget2017;8:73925-37 PMCID:PMC5650312

[61] Lee TW,Dickson BD,Cheng GJ.Radiosensitization of head and neck squamous cell carcinoma lines by DNA-PK inhibitors is more effective than PARP-1 inhibition and is enhanced by SLFN11 and hypoxia..Int J Radiat Biol2019;1-16

[62] Borst GR,Kyula JN,Khan A.Targeted radiosensitization by the Chk1 inhibitor SAR-020106..Int J Radiat Oncol Biol Phys2013;85:1110-8

[63] Barker HE,McLaughlin M,Zaidi S.CHK1 inhibition radiosensitizes head and neck cancers to paclitaxel-based chemoradiotherapy..Mol Cancer Ther2016;15:2042-54

[64] Sankunny M,Lewis DW,Saunders WS.Targeted inhibition of ATR or CHEK1 reverses radioresistance in oral squamous cell carcinoma cells with distal chromosome arm 11q loss..Genes Chromosomes Cancer2014;53:129-43 PMCID:PMC4216593

[65] Busch CJ,Laban S,Knecht R.HPV-positive HNSCC cell lines but not primary human fibroblasts are radiosensitized by the inhibition of Chk1..Radiother Oncol2013;108:495-9

[66] Busch CJ,Jensen J,Gatzemeier F.G2-checkpoint targeting and radiosensitization of HPV/p16-positive HNSCC cells through the inhibition of Chk1 and Wee1..Radiother Oncol2017;122:260-6

[67] Gottgens EL,Leszczynska KB,Span PN.Inhibition of CDK4/CDK6 enhances radiosensitivity of HPV negative head and neck squamous cell carcinomas..Int J Radiat Oncol Biol Phys2019;105:548-58

[68] Dassonville O,Francoual M,Santini J.Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer..J Clin Oncol1993;11:1873-8

[69] Magne N,Bensadoun RJ,Poissonnet G.The relationship of epidermal growth factor receptor levels to the prognosis of unresectable pharyngeal cancer patients treated by chemo-radiotherapy..Eur J Cancer2001;37:2169-77

[70] Pivot X,Guardiola E,Dassonville O.Prognostic impact of the epidermal growth factor receptor levels for patients with larynx and hypopharynx cancer..Oral Oncol2005;41:320-7

[71] Kalyankrishna S.Epidermal growth factor receptor biology in head and neck cancer..J Clin Oncol2006;24:2666-72

[72] Harari PM,Grandis JR.Molecular target approaches in head and neck cancer: epidermal growth factor receptor and beyond..Semin Radiat Oncol2009;19:63-8 PMCID:PMC3216119

[73] Byeon HK,Yang J.Beyond EGFR inhibition: multilateral combat strategies to stop the progression of head and neck cancer..Exp Mol Med2019;51:1-14 PMCID:PMC6353966

[74] Bonner JA,Giralt J,Shin DM.Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck..N Engl J Med2006;354:567-78

[75] Tang C,Jiang W,von Eyben R.Concurrent cetuximab versus platinum-based chemoradiation for the definitive treatment of locoregionally advanced head and neck cancer..Head Neck2015;37:386-92

[76] Stegeman H,Cockx SC,Rijken PF.EGFR-inhibition enhances apoptosis in irradiated human head and neck xenograft tumors independent of effects on DNA repair..Radiat Res2013;180:414-21

[77] Gillison ML,Harris J,Harari PM.Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial..Lancet2019;393:40-50 PMCID:PMC6541928

[78] Mehanna H,Hartley A,Foran B.Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial..Lancet2019;393:51-60 PMCID:PMC6319250

[79] Rieckmann T.The failure of cetuximab-based de-intensified regimes for HPV-positive OPSCC: a radiobiologists perspective..Clin Transl Radiat Oncol2019;17:47-50 PMCID:PMC6558227

[80] Martinez-Useros J.The challenge of blocking a wider family members of EGFR against head and neck squamous cell carcinomas..Oral Oncol2015;51:423-30

[81] Gurtner K,Butof R,Eicheler W.Diverse effects of combined radiotherapy and EGFR inhibition with antibodies or TK inhibitors on local tumour control and correlation with EGFR gene expression..Radiother Oncol2011;99:323-30

[82] Kriegs M,Riepen B,Struve N.Radiosensitization of HNSCC cells by EGFR inhibition depends on the induction of cell cycle arrests..Oncotarget2016;7:45122-33 PMCID:PMC5216710

[83] Burtness B,Dinis J,Yokota T.Afatinib vs Placebo as adjuvant therapy after chemoradiotherapy in squamous cell carcinoma of the head and neck: a randomized clinical trial..JAMA Oncol2019;5:1170-80 PMCID:PMC6567846

[84] Guo Y,Chan A,Kang JH.Afatinib versus methotrexate as second-line treatment in Asian patients with recurrent or metastatic squamous cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 3): an open-label, randomised phase III trial..Ann Oncol2019;30:1831-9 PMCID:PMC6927323

[85] Khaznadar SS,Schmid E,Becker ET.EGFR overexpression is not common in patients with head and neck cancer. Cell lines are not representative for the clinical situation in this indication..Oncotarget2018;9:28965-75 PMCID:PMC6034751

[86] Kriegs M,Hoffer K,Buhs S.Analyzing expression and phosphorylation of the EGF receptor in HNSCC..Sci Rep2019;9:13564 PMCID:PMC6753061

[87] Curtis KK,Ross HJ.Past approaches and future directions for targeting tumor hypoxia in squamous cell carcinomas of the head and neck..Crit Rev Oncol Hematol2016;103:86-98

[88] Lee DJ,Marcial VA,Rotman M.Results of an RTOG phase III trial (RTOG 85-27) comparing radiotherapy plus etanidazole with radiotherapy alone for locally advanced head and neck carcinomas..Int J Radiat Oncol Biol Phys1995;32:567-76

[89] Overgaard J,Overgaard M,Berthelsen A.A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85..Radiother Oncol1998;46:135-46

[90] Toustrup K,Lassen P,Alsner J.Gene expression classifier predicts for hypoxic modification of radiotherapy with nimorazole in squamous cell carcinomas of the head and neck..Radiother Oncol2012;102:122-9

[91] Lassen P,Hamilton-Dutoit S,Alsner J.HPV-associated p16-expression and response to hypoxic modification of radiotherapy in head and neck cancer..Radiother Oncol2010;94:30-5

[92] NIMRAD (A Randomised Placebo-controlled Trial of Synchronous NIMorazole Versus RADiotherapy Alone in Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma Not Suitable for Synchronous Chemotherapy or Cetuximab) NIMRAD. The Christie NHS Foundation Trust; 2014. Available from: https://clinicaltrials.gov/ct2/show/NCT01950689. [Last accessed on 9 Sep 2020]

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

[94] McKeage MJ.Disrupting established tumor blood vessels: an emerging therapeutic strategy for cancer..Cancer2010;116:1859-71

[95] Seshadri M,Spernyak JA,Rustum YM.Activity of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid against human head and neck carcinoma xenografts..Neoplasia2006;8:534-42 PMCID:PMC1601938

[96] Wilson WR,Cowan DS.Enhancement of tumor radiation response by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid..Int J Radiat Oncol Biol Phys1998;42:905-8

[97] Parsons JL.Co-ordination of base excision repair and genome stability..DNA Repair (Amst)2013;12:326-33

[98] Dianov GL.Co-ordination of DNA single strand break repair..DNA Repair (Amst)2007;6:454-60

[99] Ray Chaudhuri A.The multifaceted roles of PARP1 in DNA repair and chromatin remodelling..Nat Rev Mol Cell Biol2017;18:610-21 PMCID:PMC6591728

[100] Farmer H,Lord CJ,Johnson DA.Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy..Nature2005;434:917-21

[101] Bryant HE,Thomas HD,Flower D.Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase..Nature2005;434:913-7

[102] Kong A,Kirkham A,Mant R.Phase I trial of WEE1 inhibition with chemotherapy and radiotherapy as adjuvant treatment, and a window of opportunity trial with cisplatin in patients with head and neck cancer: the WISTERIA trial protocol..BMJ Open2020;10:e033009 PMCID:PMC7076237

[103] Seront E,Papier M,Henry S.Phase 1 study evaluating the association of the cyclin-dependent kinase 4/6 inhibitor Ribociclib and Cetuximab in recurrent/metastatic p16-negative squamous cell carcinoma of the head and neck..Front Oncol2019;9:155 PMCID:PMC6433958

[104] Lin CJ,Carey TE,Whiteside TL.Head and neck squamous cell carcinoma cell lines: established models and rationale for selection..Head Neck2007;29:163-88

[105] Tanaka N,Takahashi Y,Patel AA.Head and neck cancer organoids established by modification of the CTOS method can be used to predict in vivo drug sensitivity..Oral Oncol2018;87:49-57 PMCID:PMC6294331

[106] Driehuis E,Spelier S,Willems SM.Oral mucosal organoids as a potential platform for personalized cancer therapy..Cancer Discov2019;9:852-71