dc.contributor.author | Tacconi, EM | |
dc.contributor.author | Badie, S | |
dc.contributor.author | De Gregoriis, G | |
dc.contributor.author | Reisländer, T | |
dc.contributor.author | Lai, X | |
dc.contributor.author | Porru, M | |
dc.contributor.author | Folio, C | |
dc.contributor.author | Moore, J | |
dc.contributor.author | Kopp, A | |
dc.contributor.author | Baguña Torres, J | |
dc.contributor.author | Sneddon, D | |
dc.contributor.author | Green, M | |
dc.contributor.author | Dedic, S | |
dc.contributor.author | Lee, JW | |
dc.contributor.author | Batra, AS | |
dc.contributor.author | Rueda, OM | |
dc.contributor.author | Bruna, A | |
dc.contributor.author | Leonetti, C | |
dc.contributor.author | Caldas, C | |
dc.contributor.author | Cornelissen, B | |
dc.contributor.author | Brino, L | |
dc.contributor.author | Ryan, A | |
dc.contributor.author | Biroccio, A | |
dc.contributor.author | Tarsounas, M | |
dc.date.accessioned | 2020-08-28T09:44:15Z | |
dc.date.issued | 2019-07-01 | |
dc.identifier.citation | EMBO molecular medicine, 2019, 11 (7), pp. e9982 - ? | |
dc.identifier.issn | 1757-4676 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4054 | |
dc.identifier.eissn | 1757-4684 | |
dc.identifier.doi | 10.15252/emmm.201809982 | |
dc.description.abstract | Due 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.format | Print-Electronic | |
dc.format.extent | e9982 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | WILEY | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Mice, SCID | |
dc.subject | Chlorambucil | |
dc.subject | Piperazines | |
dc.subject | Phthalazines | |
dc.subject | BRCA1 Protein | |
dc.subject | BRCA2 Protein | |
dc.subject | Peroxisome Proliferator-Activated Receptors | |
dc.subject | Drug Delivery Systems | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Cricetinae | |
dc.subject | Male | |
dc.subject | Leukemia, Lymphocytic, Chronic, B-Cell | |
dc.title | Chlorambucil targets BRCA1/2-deficient tumours and counteracts PARP inhibitor resistance. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2019-05-03 | |
rioxxterms.versionofrecord | 10.15252/emmm.201809982 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-07 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | EMBO molecular medicine | |
pubs.issue | 7 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 11 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Preclinical Modelling of Paediatric Cancer Evolution | |
dc.contributor.icrauthor | Bruna Cabot, Alejandra | |