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dc.contributor.authorDréan, A
dc.contributor.authorWilliamson, CT
dc.contributor.authorBrough, R
dc.contributor.authorBrandsma, I
dc.contributor.authorMenon, M
dc.contributor.authorKonde, A
dc.contributor.authorGarcia-Murillas, I
dc.contributor.authorPemberton, HN
dc.contributor.authorFrankum, J
dc.contributor.authorRafiq, R
dc.contributor.authorBadham, N
dc.contributor.authorCampbell, J
dc.contributor.authorGulati, A
dc.contributor.authorTurner, NC
dc.contributor.authorPettitt, SJ
dc.contributor.authorAshworth, A
dc.contributor.authorLord, CJ
dc.date.accessioned2017-09-08T11:11:24Z
dc.date.issued2017-09-01
dc.identifier.citationMolecular cancer therapeutics, 2017, 16 (9), pp. 2022 - 2034
dc.identifier.issn1535-7163
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/816
dc.identifier.eissn1538-8514
dc.identifier.doi10.1158/1535-7163.mct-17-0098
dc.description.abstractAlthough PARP inhibitors target BRCA1- or BRCA2-mutant tumor cells, drug resistance is a problem. PARP inhibitor resistance is sometimes associated with the presence of secondary or "revertant" mutations in BRCA1 or BRCA2 Whether secondary mutant tumor cells are selected for in a Darwinian fashion by treatment is unclear. Furthermore, how PARP inhibitor resistance might be therapeutically targeted is also poorly understood. Using CRISPR mutagenesis, we generated isogenic tumor cell models with secondary BRCA1 or BRCA2 mutations. Using these in heterogeneous in vitro culture or in vivo xenograft experiments in which the clonal composition of tumor cell populations in response to therapy was monitored, we established that PARP inhibitor or platinum salt exposure selects for secondary mutant clones in a Darwinian fashion, with the periodicity of PARP inhibitor administration and the pretreatment frequency of secondary mutant tumor cells influencing the eventual clonal composition of the tumor cell population. In xenograft studies, the presence of secondary mutant cells in tumors impaired the therapeutic effect of a clinical PARP inhibitor. However, we found that both PARP inhibitor-sensitive and PARP inhibitor-resistant BRCA2 mutant tumor cells were sensitive to AZD-1775, a WEE1 kinase inhibitor. In mice carrying heterogeneous tumors, AZD-1775 delivered a greater therapeutic benefit than olaparib treatment. This suggests that despite the restoration of some BRCA1 or BRCA2 gene function in "revertant" tumor cells, vulnerabilities still exist that could be therapeutically exploited. Mol Cancer Ther; 16(9); 2022-34. ©2017 AACR.
dc.formatPrint-Electronic
dc.format.extent2022 - 2034
dc.languageeng
dc.language.isoeng
dc.publisherAMER ASSOC CANCER RESEARCH
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectDisease Models, Animal
dc.subjectPyrazoles
dc.subjectPyrimidines
dc.subjectPyrimidinones
dc.subjectCell Cycle Proteins
dc.subjectBRCA1 Protein
dc.subjectBRCA2 Protein
dc.subjectNuclear Proteins
dc.subjectAntineoplastic Agents
dc.subjectXenograft Model Antitumor Assays
dc.subjectDNA Mutational Analysis
dc.subjectCell Cycle
dc.subjectDrug Resistance, Neoplasm
dc.subjectMutation
dc.subjectFemale
dc.subjectProtein-Tyrosine Kinases
dc.subjectGene Knockdown Techniques
dc.subjectSelection, Genetic
dc.subjectPoly(ADP-ribose) Polymerase Inhibitors
dc.titleModeling Therapy Resistance in BRCA1/2-Mutant Cancers.
dc.typeJournal Article
dcterms.dateAccepted2017-06-05
rioxxterms.funderThe Institute of Cancer Research
rioxxterms.identifier.projectUnspecified
rioxxterms.versionofrecord10.1158/1535-7163.mct-17-0098
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2017-09
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfMolecular cancer therapeutics
pubs.issue9
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/Breast Cancer Research/Molecular Oncology
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/Breast Cancer Research/Molecular Oncology
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.volume16
pubs.embargo.termsNot known
icr.researchteamMolecular Oncology
icr.researchteamGene Function
dc.contributor.icrauthorDrean, Amy
dc.contributor.icrauthorGarcia-Murillas, Isaac
dc.contributor.icrauthorCampbell, James
dc.contributor.icrauthorTurner, Nicholas
dc.contributor.icrauthorPettitt, Stephen
dc.contributor.icrauthorLord, Christopher


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