dc.contributor.author | Frankum, J | |
dc.contributor.author | Moudry, P | |
dc.contributor.author | Brough, R | |
dc.contributor.author | Hodny, Z | |
dc.contributor.author | Ashworth, A | |
dc.contributor.author | Bartek, J | |
dc.contributor.author | Lord, CJ | |
dc.date.accessioned | 2016-09-14T09:36:06Z | |
dc.date.issued | 2015-05-10 | |
dc.identifier.citation | Oncotarget, 2015, 6 (13), pp. 10746 - 10758 | |
dc.identifier.issn | 1949-2553 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/108 | |
dc.identifier.eissn | 1949-2553 | |
dc.identifier.doi | 10.18632/oncotarget.3628 | |
dc.description.abstract | Based on a series of basic, preclinical and clinical studies, the Poly (ADP-ribose) Polymerase 1 (PARP1) inhibitor, olaparib, has recently been approved for use in ovarian cancer patients with BRCA1 or BRCA2 mutations. By identifying novel predictive biomarkers of tumour cell sensitivity to olaparib, it is possible that the utility of PARP inhibitors could be extended beyond this patient subgroup. Many of the known genetic determinants of PARP inhibitor response have key roles in DNA damage response (DDR) pathways. Although protein ubiquitylation is known to play an important role in regulating the DDR, the exact mechanisms by which this occurs are not fully understood. Using two parallel RNA interference-based screening approaches, we identified the E3 ubiquitin ligase, CBLC, as a candidate biomarker of response to olaparib. We validated this observation by demonstrating that silencing of CBLC causes increased sensitivity to olaparib in breast cancer cell line models and that defective homologous recombination (HR) DNA repair is the likely cause. This data provides an example of how defects in the ubiquitin machinery have the potential to influence the response of tumour cells to PARP inhibitors. | |
dc.format | Print | |
dc.format.extent | 10746 - 10758 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | IMPACT JOURNALS LLC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Humans | |
dc.subject | Breast Neoplasms | |
dc.subject | Piperazines | |
dc.subject | Phthalazines | |
dc.subject | Poly(ADP-ribose) Polymerases | |
dc.subject | BRCA2 Protein | |
dc.subject | Transfection | |
dc.subject | Signal Transduction | |
dc.subject | Cell Survival | |
dc.subject | DNA Repair | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | RNA Interference | |
dc.subject | Protein Processing, Post-Translational | |
dc.subject | Recombination, Genetic | |
dc.subject | Dose-Response Relationship, Drug | |
dc.subject | Time Factors | |
dc.subject | Female | |
dc.subject | Proto-Oncogene Proteins c-cbl | |
dc.subject | Ubiquitination | |
dc.subject | Poly(ADP-ribose) Polymerase Inhibitors | |
dc.subject | Poly (ADP-Ribose) Polymerase-1 | |
dc.title | Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2015-02-20 | |
rioxxterms.versionofrecord | 10.18632/oncotarget.3628 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2015-05 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Oncotarget | |
pubs.issue | 13 | |
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/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/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.publication-status | Published | |
pubs.volume | 6 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Lord, Christopher | |