dc.contributor.author | Carmichael, J | |
dc.contributor.author | Figueiredo, I | |
dc.contributor.author | Gurel, B | |
dc.contributor.author | Beije, N | |
dc.contributor.author | Yuan, W | |
dc.contributor.author | Rekowski, J | |
dc.contributor.author | Seed, G | |
dc.contributor.author | Carreira, S | |
dc.contributor.author | Bertan, C | |
dc.contributor.author | Fenor de la Maza, MDLD | |
dc.contributor.author | Chandran, K | |
dc.contributor.author | Neeb, A | |
dc.contributor.author | Welti, J | |
dc.contributor.author | Gallagher, L | |
dc.contributor.author | Bogdan, D | |
dc.contributor.author | Crespo, M | |
dc.contributor.author | Riisnaes, R | |
dc.contributor.author | Ferreira, A | |
dc.contributor.author | Miranda, S | |
dc.contributor.author | Lu, J | |
dc.contributor.author | Shen, MM | |
dc.contributor.author | Hall, E | |
dc.contributor.author | Porta, N | |
dc.contributor.author | Westaby, D | |
dc.contributor.author | Guo, C | |
dc.contributor.author | Grochot, R | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Mateo, J | |
dc.contributor.author | Sharp, A | |
dc.contributor.author | de Bono, J | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2024-08-09T11:07:48Z | |
dc.date.available | 2024-08-09T11:07:48Z | |
dc.date.issued | 2024-06-04 | |
dc.identifier | 178278 | |
dc.identifier.citation | Journal of Clinical Investigation, 2024, pp. e178278 - | |
dc.identifier.issn | 0021-9738 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/6345 | |
dc.identifier.eissn | 1558-8238 | |
dc.identifier.eissn | 1558-8238 | |
dc.identifier.doi | 10.1172/JCI178278 | |
dc.identifier.doi | 10.1172/JCI178278 | |
dc.description.abstract | BACKGROUND: Clinical trials have suggested antitumor activity from PARP inhibition beyond homologous recombination deficiency (HRD). RNASEH2B loss is unrelated to HRD and preclinically sensitizes to PARP inhibition. The current study reports on RNASEH2B protein loss in advanced prostate cancer and its association with RB1 protein loss, clinical outcome and clonal dynamics during treatment with PARP inhibition in a prospective clinical trial. METHODS: Whole tumor biopsies from multiple cohorts of patients with advanced prostate cancer were interrogated using whole-exome sequencing (WES), RNA sequencing (bulk and single nucleus) and immunohistochemistry (IHC) for RNASEH2B and RB1. Biopsies from patients treated with olaparib in the TOPARP-A and TOPARP-B clinical trials were used to evaluate RNASEH2B clonal selection during olaparib treatment. RESULTS: Shallow co-deletion of RNASEH2B and adjacent RB1, co-located at chromosome 13q14, was common, deep co-deletion infrequent, and gene loss associated with lower mRNA expression. In castration-resistant PC (CRPC) biopsies, RNASEH2B and RB1 mRNA expression correlated, but single nucleus RNA sequencing indicated discordant loss of expression. IHC studies showed that loss of the two proteins often occurred independently, arguably due to stochastic second allele loss. Pre- and post-treatment metastatic CRPC (mCRPC) biopsy studies from BRCA1/2 wildtype tumors, treated on the TOPARP phase II trial, indicated that olaparib eradicates RNASEH2B-loss tumor subclones. CONCLUSION: PARP inhibition may benefit men suffering from mCRPC by eradicating tumor subclones with RNASEH2B loss. CLINICALTRIALS: gov NCT01682772FUNDING. AstraZeneca; Cancer Research UK; Medical Research Council; Cancer Research UK; Prostate Cancer UK; Movember Foundation; Prostate Cancer Foundation. | |
dc.format | Print-Electronic | |
dc.format.extent | e178278 - | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | American Society for Clinical Investigation | |
dc.relation.ispartof | Journal of Clinical Investigation | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Oncology | |
dc.subject | Prostate cancer | |
dc.title | RNASEH2B loss and PARP inhibition in advanced prostate cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2024-06-04 | |
dc.date.updated | 2024-08-08T09:34:05Z | |
rioxxterms.version | AM | |
rioxxterms.versionofrecord | 10.1172/JCI178278 | |
rioxxterms.licenseref.startdate | 2024-06-04 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/38833311 | |
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 Therapeutics | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit | |
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/Clinical Studies/Translational Therapeutics | |
pubs.organisational-group | ICR/Students | |
pubs.organisational-group | ICR/Students/PhD and MPhil | |
pubs.organisational-group | ICR/Students/PhD and MPhil/18/19 Starting Cohort | |
pubs.organisational-group | ICR/Students/PhD and MPhil/20/21 Starting Cohort | |
pubs.organisational-group | ICR/Students/PhD and MPhil/22/23 Starting Cohort | |
pubs.publication-status | Published online | |
pubs.publisher-url | http://dx.doi.org/10.1172/jci178278 | |
icr.researchteam | Cancer Biomarkers | |
icr.researchteam | Clin Trials & Stats Unit | |
icr.researchteam | Translational Therapeutic | |
icr.researchteam | Gene Function | |
icr.researchteam | PrCa Targeted Therapy | |
dc.contributor.icrauthor | Gurel, Bora | |
dc.contributor.icrauthor | Carreira, Suzanne | |
dc.contributor.icrauthor | Gallagher, Lewis | |
dc.contributor.icrauthor | Bogdan, Denisa Ioana | |
dc.contributor.icrauthor | Crespo, Mateus | |
dc.contributor.icrauthor | Miranda, Susana | |
dc.contributor.icrauthor | Hall, Emma | |
dc.contributor.icrauthor | Porta, Nuria | |
dc.contributor.icrauthor | Westaby, Daniel | |
dc.contributor.icrauthor | Lord, Christopher | |
dc.contributor.icrauthor | Sharp, Adam | |
dc.contributor.icrauthor | De Bono, Johann | |
icr.provenance | Deposited by Ms Jessica Phelps (impersonating Prof Emma Hall) on 2024-08-08. Deposit type is initial. No. of files: 1. Files: RNASEH2B loss and PARP inhibition in advanced prostate cancer..pdf | |