dc.contributor.author | Bland, P | |
dc.contributor.author | Saville, H | |
dc.contributor.author | Wai, PT | |
dc.contributor.author | Curnow, L | |
dc.contributor.author | Muirhead, G | |
dc.contributor.author | Nieminuszczy, J | |
dc.contributor.author | Ravindran, N | |
dc.contributor.author | John, MB | |
dc.contributor.author | Hedayat, S | |
dc.contributor.author | Barker, HE | |
dc.contributor.author | Wright, J | |
dc.contributor.author | Yu, L | |
dc.contributor.author | Mavrommati, I | |
dc.contributor.author | Read, A | |
dc.contributor.author | Peck, B | |
dc.contributor.author | Allen, M | |
dc.contributor.author | Gazinska, P | |
dc.contributor.author | Pemberton, HN | |
dc.contributor.author | Gulati, A | |
dc.contributor.author | Nash, S | |
dc.contributor.author | Noor, F | |
dc.contributor.author | Guppy, N | |
dc.contributor.author | Roxanis, I | |
dc.contributor.author | Pratt, G | |
dc.contributor.author | Oldreive, C | |
dc.contributor.author | Stankovic, T | |
dc.contributor.author | Barlow, S | |
dc.contributor.author | Kalirai, H | |
dc.contributor.author | Coupland, SE | |
dc.contributor.author | Broderick, R | |
dc.contributor.author | Alsafadi, S | |
dc.contributor.author | Houy, A | |
dc.contributor.author | Stern, M-H | |
dc.contributor.author | Pettit, S | |
dc.contributor.author | Choudhary, JS | |
dc.contributor.author | Haider, S | |
dc.contributor.author | Niedzwiedz, W | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Natrajan, R | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2023-09-05T09:32:04Z | |
dc.date.available | 2023-09-05T09:32:04Z | |
dc.date.issued | 2023-08-01 | |
dc.identifier | 10.1038/s41588-023-01460-5 | |
dc.identifier.citation | Nature Genetics, 2023, 55 (8), pp. 1311 - 1323 | |
dc.identifier.issn | 1061-4036 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5950 | |
dc.identifier.eissn | 1546-1718 | |
dc.identifier.eissn | 1546-1718 | |
dc.identifier.doi | 10.1038/s41588-023-01460-5 | |
dc.description.abstract | SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUT cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUT cancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population. | |
dc.format | Print-Electronic | |
dc.format.extent | 1311 - 1323 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PORTFOLIO | |
dc.relation.ispartof | Nature Genetics | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Humans | |
dc.subject | Poly(ADP-ribose) Polymerase Inhibitors | |
dc.subject | Mutation | |
dc.subject | Transcription Factors | |
dc.subject | Neoplasms | |
dc.subject | BRCA1 Protein | |
dc.subject | Cell Line, Tumor | |
dc.subject | RNA Splicing Factors | |
dc.subject | Phosphoproteins | |
dc.title | SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2023-06-26 | |
dc.date.updated | 2023-09-05T09:14:29Z | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1038/s41588-023-01460-5 | |
rioxxterms.licenseref.startdate | 2023-08-01 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/37524790 | |
pubs.issue | 8 | |
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/Functional Genomics | |
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/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Cancer and Genome Instability | |
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/s41588-023-01460-5 | |
pubs.volume | 55 | |
icr.researchteam | Functional Proteomics | |
icr.researchteam | Prote & Metabolomics Fac | |
icr.researchteam | BCR Bioinformatics Group | |
icr.researchteam | Cancer and Genome Instab | |
icr.researchteam | Gene Function | |
icr.researchteam | Functional Genomics | |
dc.contributor.icrauthor | Wright, James | |
dc.contributor.icrauthor | Roxanis, Ioannis | |
dc.contributor.icrauthor | Choudhary, Jyoti | |
dc.contributor.icrauthor | Haider, Syed | |
dc.contributor.icrauthor | Niedzwiedz, Wojciech | |
dc.contributor.icrauthor | Lord, Christopher | |
dc.contributor.icrauthor | Natrajan, Rachael | |
icr.provenance | Deposited by Ms Alex Carroll (impersonating Dr Syed Haider) on 2023-09-05. Deposit type is initial. No. of files: 1. Files: SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.pdf | |