dc.contributor.author | Pettitt, SJ | |
dc.contributor.author | Shao, N | |
dc.contributor.author | Zatreanu, D | |
dc.contributor.author | Frankum, J | |
dc.contributor.author | Bajrami, I | |
dc.contributor.author | Brough, R | |
dc.contributor.author | Krastev, DB | |
dc.contributor.author | Roumeliotis, TI | |
dc.contributor.author | Choudhary, JS | |
dc.contributor.author | Lorenz, S | |
dc.contributor.author | Rust, A | |
dc.contributor.author | de Bono, JS | |
dc.contributor.author | Yap, TA | |
dc.contributor.author | Tutt, ANJ | |
dc.contributor.author | Lord, CJ | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2023-09-22T12:39:42Z | |
dc.date.available | 2023-09-22T12:39:42Z | |
dc.date.issued | 2023-09-01 | |
dc.identifier | 10.1038/s41388-023-02782-8 | |
dc.identifier.citation | Oncogene, 2023, 42 (36), pp. 2701 - 2709 | en_US |
dc.identifier.issn | 0950-9232 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5981 | |
dc.identifier.eissn | 1476-5594 | |
dc.identifier.eissn | 1476-5594 | |
dc.identifier.doi | 10.1038/s41388-023-02782-8 | |
dc.description.abstract | Although PARP inhibitors (PARPi) now form part of the standard-of-care for the treatment of homologous recombination defective cancers, de novo and acquired resistance limits their overall effectiveness. Previously, overexpression of the BRCA1-∆11q splice variant has been shown to cause PARPi resistance. How cancer cells achieve increased BRCA1-∆11q expression has remained unclear. Using isogenic cells with different BRCA1 mutations, we show that reduction in HUWE1 leads to increased levels of BRCA1-∆11q and PARPi resistance. This effect is specific to cells able to express BRCA1-∆11q (e.g. BRCA1 exon 11 mutant cells) and is not seen in BRCA1 mutants that cannot express BRCA1-∆11q, nor in BRCA2 mutant cells. As well as increasing levels of BRCA1-∆11q protein in exon 11 mutant cells, HUWE1 silencing also restores RAD51 nuclear foci and platinum salt resistance. HUWE1 catalytic domain mutations were also seen in a case of PARPi resistant, BRCA1 exon 11 mutant, high grade serous ovarian cancer. These results suggest how elevated levels of BRCA1-∆11q and PARPi resistance can be achieved, identify HUWE1 as a candidate biomarker of PARPi resistance for assessment in future clinical trials and illustrate how some PARPi resistance mechanisms may only operate in patients with particular BRCA1 mutations. | |
dc.format | Print-Electronic | |
dc.format.extent | 2701 - 2709 | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | SPRINGERNATURE | en_US |
dc.relation.ispartof | Oncogene | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Humans | |
dc.subject | Female | |
dc.subject | Poly(ADP-ribose) Polymerase Inhibitors | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Antineoplastic Agents | |
dc.subject | BRCA1 Protein | |
dc.subject | BRCA2 Protein | |
dc.subject | Mutation | |
dc.subject | Neoplasms | |
dc.subject | Ovarian Neoplasms | |
dc.subject | Tumor Suppressor Proteins | |
dc.subject | Ubiquitin-Protein Ligases | |
dc.title | A HUWE1 defect causes PARP inhibitor resistance by modulating the BRCA1-∆11q splice variant. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2023-07-12 | |
dc.date.updated | 2023-09-22T12:39:20Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1038/s41388-023-02782-8 | en_US |
rioxxterms.licenseref.startdate | 2023-09-01 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/37491606 | |
pubs.issue | 36 | |
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/Cancer Biology | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
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/Primary Group/ICR Divisions/Cancer Biology/Functional Proteomics Group | |
pubs.organisational-group | ICR/ImmNet | |
pubs.publication-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1038/s41388-023-02782-8 | |
pubs.volume | 42 | |
icr.researchteam | Gene Function | en_US |
icr.researchteam | Functional Proteomics | en_US |
icr.researchteam | Prote & Metabolomics Fac | en_US |
icr.researchteam | PrCa Targeted Therapy | en_US |
icr.researchteam | Directorate Breast Canc | en_US |
dc.contributor.icrauthor | Pettitt, Stephen | |
dc.contributor.icrauthor | Krastev, Dragomir | |
dc.contributor.icrauthor | Roumeliotis, Theodoros | |
dc.contributor.icrauthor | Choudhary, Jyoti | |
dc.contributor.icrauthor | De Bono, Johann | |
dc.contributor.icrauthor | Tutt, Andrew | |
dc.contributor.icrauthor | Lord, Christopher | |
icr.provenance | Deposited by Mr Arek Surman (impersonating Prof Johann De Bono) on 2023-09-22. Deposit type is initial. No. of files: 1. Files: A HUWE1 defect causes PARP inhibitor resistance by modulating the BRCA1-∆11q splice variant.pdf | |