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dc.contributor.authorZatreanu, D
dc.contributor.authorRobinson, HMR
dc.contributor.authorAlkhatib, O
dc.contributor.authorBoursier, M
dc.contributor.authorFinch, H
dc.contributor.authorGeo, L
dc.contributor.authorGrande, D
dc.contributor.authorGrinkevich, V
dc.contributor.authorHeald, RA
dc.contributor.authorLangdon, S
dc.contributor.authorMajithiya, J
dc.contributor.authorMcWhirter, C
dc.contributor.authorMartin, NMB
dc.contributor.authorMoore, S
dc.contributor.authorNeves, J
dc.contributor.authorRajendra, E
dc.contributor.authorRanzani, M
dc.contributor.authorSchaedler, T
dc.contributor.authorStockley, M
dc.contributor.authorWiggins, K
dc.contributor.authorBrough, R
dc.contributor.authorSridhar, S
dc.contributor.authorGulati, A
dc.contributor.authorShao, N
dc.contributor.authorBadder, LM
dc.contributor.authorNovo, D
dc.contributor.authorKnight, EG
dc.contributor.authorMarlow, R
dc.contributor.authorHaider, S
dc.contributor.authorCallen, E
dc.contributor.authorHewitt, G
dc.contributor.authorSchimmel, J
dc.contributor.authorPrevo, R
dc.contributor.authorAlli, C
dc.contributor.authorFerdinand, A
dc.contributor.authorBell, C
dc.contributor.authorBlencowe, P
dc.contributor.authorBot, C
dc.contributor.authorCalder, M
dc.contributor.authorCharles, M
dc.contributor.authorCurry, J
dc.contributor.authorEkwuru, T
dc.contributor.authorEwings, K
dc.contributor.authorKrajewski, W
dc.contributor.authorMacDonald, E
dc.contributor.authorMcCarron, H
dc.contributor.authorPang, L
dc.contributor.authorPedder, C
dc.contributor.authorRigoreau, L
dc.contributor.authorSwarbrick, M
dc.contributor.authorWheatley, E
dc.contributor.authorWillis, S
dc.contributor.authorWong, AC
dc.contributor.authorNussenzweig, A
dc.contributor.authorTijsterman, M
dc.contributor.authorTutt, A
dc.contributor.authorBoulton, SJ
dc.contributor.authorHiggins, GS
dc.contributor.authorPettitt, SJ
dc.contributor.authorSmith, GCM
dc.contributor.authorLord, CJ
dc.date.accessioned2021-08-13T08:20:22Z
dc.date.available2021-08-13T08:20:22Z
dc.date.issued2021-06-17
dc.identifier.citationNature communications, 2021, 12 (1), pp. 3636 - ?
dc.identifier.issn2041-1723
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4762
dc.identifier.eissn2041-1723
dc.identifier.eissn2041-1723en_US
dc.identifier.doi10.1038/s41467-021-23463-8
dc.identifier.doi10.1038/s41467-021-23463-8en_US
dc.description.abstractTo identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining, without targeting Non-Homologous End Joining. In addition, ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a PARP inhibitor. Genetic perturbation screening revealed that defects in the 53BP1/Shieldin complex, which cause PARP inhibitor resistance, result in in vitro and in vivo sensitivity to small molecule Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells whilst the inhibition of DNA nucleases that promote end-resection reversed these effects, implicating these in the synthetic lethal mechanism-of-action. Taken together, these observations describe a drug class that elicits BRCA-gene synthetic lethality and PARP inhibitor synergy, as well as targeting a biomarker-defined mechanism of PARPi-resistance.
dc.formatElectronic
dc.format.extent3636 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectOrganoids
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectRats
dc.subjectOvarian Neoplasms
dc.subjectDNA Damage
dc.subjectDeoxyribonucleases
dc.subjectDNA-Directed DNA Polymerase
dc.subjectCell Cycle Proteins
dc.subjectDNA-Binding Proteins
dc.subjectBRCA1 Protein
dc.subjectBRCA2 Protein
dc.subjectNucleic Acid Synthesis Inhibitors
dc.subjectDrug Screening Assays, Antitumor
dc.subjectInhibitory Concentration 50
dc.subjectApoptosis
dc.subjectCell Proliferation
dc.subjectCell Survival
dc.subjectDNA Repair
dc.subjectAllosteric Regulation
dc.subjectDrug Resistance, Neoplasm
dc.subjectFemale
dc.subjectHomologous Recombination
dc.subjectPoly(ADP-ribose) Polymerase Inhibitors
dc.subjectTumor Suppressor p53-Binding Protein 1
dc.subjectSynthetic Lethal Mutations
dc.titlePolθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.
dc.typeJournal Article
dcterms.dateAccepted2021-04-30
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41467-021-23463-8
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2021-06-17
rioxxterms.licenseref.startdate2021-06-17en_US
dc.relation.isPartOfNature communications
pubs.issue1
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.publication-statusPublished
pubs.volume12en_US
pubs.embargo.termsNot known
icr.researchteamGene Function
icr.researchteamGene Functionen_US
dc.contributor.icrauthorHaider, Syeden
dc.contributor.icrauthorPettitt, Stephenen
dc.contributor.icrauthorLord, Christopheren


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