dc.contributor.author | Hedayat, S | |
dc.contributor.author | Cascione, L | |
dc.contributor.author | Cunningham, D | |
dc.contributor.author | Schirripa, M | |
dc.contributor.author | Lampis, A | |
dc.contributor.author | Hahne, JC | |
dc.contributor.author | Tunariu, N | |
dc.contributor.author | Hong, SP | |
dc.contributor.author | Marchetti, S | |
dc.contributor.author | Khan, K | |
dc.contributor.author | Fontana, E | |
dc.contributor.author | Angerilli, V | |
dc.contributor.author | Delrieux, M | |
dc.contributor.author | Nava Rodrigues, D | |
dc.contributor.author | Procaccio, L | |
dc.contributor.author | Rao, S | |
dc.contributor.author | Watkins, D | |
dc.contributor.author | Starling, N | |
dc.contributor.author | Chau, I | |
dc.contributor.author | Braconi, C | |
dc.contributor.author | Fotiadis, N | |
dc.contributor.author | Begum, R | |
dc.contributor.author | Guppy, N | |
dc.contributor.author | Howell, L | |
dc.contributor.author | Valenti, M | |
dc.contributor.author | Cribbes, S | |
dc.contributor.author | Kolozsvari, B | |
dc.contributor.author | Kirkin, V | |
dc.contributor.author | Lonardi, S | |
dc.contributor.author | Ghidini, M | |
dc.contributor.author | Passalacqua, R | |
dc.contributor.author | Elghadi, R | |
dc.contributor.author | Magnani, L | |
dc.contributor.author | Pinato, DJ | |
dc.contributor.author | Di Maggio, F | |
dc.contributor.author | Ghelardi, F | |
dc.contributor.author | Sottotetti, E | |
dc.contributor.author | Vetere, G | |
dc.contributor.author | Ciracì, P | |
dc.contributor.author | Vlachogiannis, G | |
dc.contributor.author | Pietrantonio, F | |
dc.contributor.author | Cremolini, C | |
dc.contributor.author | Cortellini, A | |
dc.contributor.author | Loupakis, F | |
dc.contributor.author | Fassan, M | |
dc.contributor.author | Valeri, N | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2024-05-20T11:19:23Z | |
dc.date.available | 2024-05-20T11:19:23Z | |
dc.date.issued | 2024-05-15 | |
dc.identifier | 734699 | |
dc.identifier.citation | Clinical Cancer Research, 2024, pp. OF1 - OF20 | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/6235 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.doi | 10.1158/1078-0432.CCR-23-2748 | |
dc.identifier.doi | 10.1158/1078-0432.CCR-23-2748 | |
dc.description.abstract | PURPOSE: The multi-kinase inhibitor (mKi) regorafenib has demonstrated efficacy in chemorefractory patients with metastatic colorectal cancer (mCRC). However, lack of predictive biomarkers and concerns over significant toxicities hamper the use of regorafenib in clinical practice. EXPERIMENTAL DESIGN: Serial liquid biopsies were obtained at baseline and monthly until disease progression in chemorefractory patients with mCRC treated with regorafenib in a phase II clinical trial (PROSPECT-R n = 40; NCT03010722) and in a multicentric validation cohort (n = 241). Tissue biopsies collected at baseline, after 2 months and at progression in the PROSPECT-R trial were used to establish patient-derived organoids (PDO) and for molecular analyses. MicroRNA profiling was performed on baseline bloods using the NanoString nCounter platform and results were validated by digital-droplet PCR and/or ISH in paired liquid and tissue biopsies. PDOs co-cultures and PDO-xenotransplants were generated for functional analyses. RESULTS: Large-scale microRNA expression analysis in longitudinal matched liquid and tissue biopsies from the PROSPECT-R trial identified MIR652-3p as a biomarker of clinical benefit to regorafenib. These findings were confirmed in an independent validation cohort and in a "control" group of 100 patients treated with lonsurf. Using ex vivo co-culture assays paired with single-cell RNA-sequencing of PDO established pre- and post-treatment, we modeled regorafenib response observed in vivo and in patients, and showed that MIR652-3p controls resistance to regorafenib by impairing regorafenib-induced lethal autophagy and by orchestrating the switch from neo-angiogenesis to vessel co-option. CONCLUSIONS: Our results identify MIR652-3p as a potential biomarker and as a driver of cell and non-cell-autonomous mechanisms of resistance to regorafenib. | |
dc.format | Print-Electronic | |
dc.format.extent | OF1 - OF20 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.relation.ispartof | Clinical Cancer Research | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.title | Circulating microRNA Analysis in a Prospective Co-clinical Trial Identifies MIR652-3p as a Response Biomarker and Driver of Regorafenib Resistance Mechanisms in Colorectal Cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2024-02-16 | |
dc.date.updated | 2024-05-20T11:17:26Z | |
rioxxterms.version | AM | |
rioxxterms.versionofrecord | 10.1158/1078-0432.CCR-23-2748 | |
rioxxterms.licenseref.startdate | 2024-02-20 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/38376926 | |
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/Cancer Therapeutics | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham) | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Closed research teams | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.) | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials/Gastrointestinal Cancers Clinical Trials (hon.) | |
pubs.organisational-group | ICR/Students | |
pubs.organisational-group | ICR/Students/PhD and MPhil | |
pubs.organisational-group | ICR/Students/PhD and MPhil/13/14 Starting Cohort | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Closed research teams/Gastrointestinal Cancer Biology and Genomics | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Breast Cancer Research/Breast Epigenetic Plasticity and Evolution | |
pubs.publication-status | Published online | |
pubs.publisher-url | http://dx.doi.org/10.1158/1078-0432.ccr-23-2748 | |
icr.researchteam | Medicine (RMH) | |
icr.researchteam | Paediatric Tumour Biology | |
icr.researchteam | Breast Epige Plast & Evol | |
icr.researchteam | GI Cancer Biol & Genomics | |
dc.contributor.icrauthor | Lampis, Andrea | |
dc.contributor.icrauthor | Magnani, Luca | |
dc.contributor.icrauthor | Valeri, Nicola | |
icr.provenance | Deposited by Mr Arek Surman (impersonating Prof Ros Eeles) on 2024-05-20. Deposit type is initial. No. of files: 1. Files: ccr-23-2748.pdf | |