dc.contributor.author | Dréan, A | |
dc.contributor.author | Williamson, CT | |
dc.contributor.author | Brough, R | |
dc.contributor.author | Brandsma, I | |
dc.contributor.author | Menon, M | |
dc.contributor.author | Konde, A | |
dc.contributor.author | Garcia-Murillas, I | |
dc.contributor.author | Pemberton, HN | |
dc.contributor.author | Frankum, J | |
dc.contributor.author | Rafiq, R | |
dc.contributor.author | Badham, N | |
dc.contributor.author | Campbell, J | |
dc.contributor.author | Gulati, A | |
dc.contributor.author | Turner, NC | |
dc.contributor.author | Pettitt, SJ | |
dc.contributor.author | Ashworth, A | |
dc.contributor.author | Lord, CJ | |
dc.date.accessioned | 2017-09-08T11:11:24Z | |
dc.date.issued | 2017-09-01 | |
dc.identifier.citation | Molecular cancer therapeutics, 2017, 16 (9), pp. 2022 - 2034 | |
dc.identifier.issn | 1535-7163 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/816 | |
dc.identifier.eissn | 1538-8514 | |
dc.identifier.doi | 10.1158/1535-7163.mct-17-0098 | |
dc.description.abstract | Although 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.format | Print-Electronic | |
dc.format.extent | 2022 - 2034 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Disease Models, Animal | |
dc.subject | Pyrazoles | |
dc.subject | Pyrimidines | |
dc.subject | Pyrimidinones | |
dc.subject | Cell Cycle Proteins | |
dc.subject | BRCA1 Protein | |
dc.subject | BRCA2 Protein | |
dc.subject | Nuclear Proteins | |
dc.subject | Antineoplastic Agents | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | DNA Mutational Analysis | |
dc.subject | Cell Cycle | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Mutation | |
dc.subject | Female | |
dc.subject | Protein-Tyrosine Kinases | |
dc.subject | Gene Knockdown Techniques | |
dc.subject | Selection, Genetic | |
dc.subject | Poly(ADP-ribose) Polymerase Inhibitors | |
dc.title | Modeling Therapy Resistance in BRCA1/2-Mutant Cancers. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-06-05 | |
rioxxterms.funder | The Institute of Cancer Research | |
rioxxterms.identifier.project | Unspecified | |
rioxxterms.versionofrecord | 10.1158/1535-7163.mct-17-0098 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2017-09 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Molecular cancer therapeutics | |
pubs.issue | 9 | |
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/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-status | Published | |
pubs.volume | 16 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Molecular Oncology | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Drean, Amy | |
dc.contributor.icrauthor | Garcia-Murillas, Isaac | |
dc.contributor.icrauthor | Campbell, James | |
dc.contributor.icrauthor | Turner, Nicholas | |
dc.contributor.icrauthor | Pettitt, Stephen | |
dc.contributor.icrauthor | Lord, Christopher | |