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dc.contributor.authorTacconi, EM
dc.contributor.authorBadie, S
dc.contributor.authorDe Gregoriis, G
dc.contributor.authorReisländer, T
dc.contributor.authorLai, X
dc.contributor.authorPorru, M
dc.contributor.authorFolio, C
dc.contributor.authorMoore, J
dc.contributor.authorKopp, A
dc.contributor.authorBaguña Torres, J
dc.contributor.authorSneddon, D
dc.contributor.authorGreen, M
dc.contributor.authorDedic, S
dc.contributor.authorLee, JW
dc.contributor.authorBatra, AS
dc.contributor.authorRueda, OM
dc.contributor.authorBruna, A
dc.contributor.authorLeonetti, C
dc.contributor.authorCaldas, C
dc.contributor.authorCornelissen, B
dc.contributor.authorBrino, L
dc.contributor.authorRyan, A
dc.contributor.authorBiroccio, A
dc.contributor.authorTarsounas, M
dc.date.accessioned2020-08-28T09:44:15Z
dc.date.issued2019-07
dc.identifier.citationEMBO molecular medicine, 2019, 11 (7), pp. e9982 - ?
dc.identifier.issn1757-4676
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4054
dc.identifier.eissn1757-4684
dc.identifier.doi10.15252/emmm.201809982
dc.description.abstractDue to compromised homologous recombination (HR) repair, BRCA1- and BRCA2-mutated tumours accumulate DNA damage and genomic rearrangements conducive of tumour progression. To identify drugs that target specifically BRCA2-deficient cells, we screened a chemical library containing compounds in clinical use. The top hit was chlorambucil, a bifunctional alkylating agent used for the treatment of chronic lymphocytic leukaemia (CLL). We establish that chlorambucil is specifically toxic to BRCA1/2-deficient cells, including olaparib-resistant and cisplatin-resistant ones, suggesting the potential clinical use of chlorambucil against disease which has become resistant to these drugs. Additionally, chlorambucil eradicates BRCA2-deficient xenografts and inhibits growth of olaparib-resistant patient-derived tumour xenografts (PDTXs). We demonstrate that chlorambucil inflicts replication-associated DNA double-strand breaks (DSBs), similarly to cisplatin, and we identify ATR, FANCD2 and the SNM1A nuclease as determinants of sensitivity to both drugs. Importantly, chlorambucil is substantially less toxic to normal cells and tissues in vitro and in vivo relative to cisplatin. Because chlorambucil and cisplatin are equally effective inhibitors of BRCA2-compromised tumours, our results indicate that chlorambucil has a higher therapeutic index than cisplatin in targeting BRCA-deficient tumours.
dc.formatPrint-Electronic
dc.format.extente9982 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectMice, SCID
dc.subjectChlorambucil
dc.subjectPiperazines
dc.subjectPhthalazines
dc.subjectBRCA1 Protein
dc.subjectBRCA2 Protein
dc.subjectPeroxisome Proliferator-Activated Receptors
dc.subjectDrug Delivery Systems
dc.subjectXenograft Model Antitumor Assays
dc.subjectDrug Resistance, Neoplasm
dc.subjectCricetinae
dc.subjectMale
dc.subjectLeukemia, Lymphocytic, Chronic, B-Cell
dc.titleChlorambucil targets BRCA1/2-deficient tumours and counteracts PARP inhibitor resistance.
dc.typeJournal Article
dcterms.dateAccepted2019-05-03
rioxxterms.versionofrecord10.15252/emmm.201809982
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-07
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfEMBO molecular medicine
pubs.issue7
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/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Preclinical Modelling of Paediatric Cancer Evolution
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/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Preclinical Modelling of Paediatric Cancer Evolution
pubs.publication-statusPublished
pubs.volume11
pubs.embargo.termsNot known
icr.researchteamPreclinical Modelling of Paediatric Cancer Evolutionen_US
dc.contributor.icrauthorBruna Cabot, Alejandraen


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