dc.contributor.author | Mannion, J | |
dc.contributor.author | Gifford, V | |
dc.contributor.author | Bellenie, B | |
dc.contributor.author | Fernando, W | |
dc.contributor.author | Ramos Garcia, L | |
dc.contributor.author | Wilson, R | |
dc.contributor.author | John, SW | |
dc.contributor.author | Udainiya, S | |
dc.contributor.author | Patin, EC | |
dc.contributor.author | Tiu, C | |
dc.contributor.author | Smith, A | |
dc.contributor.author | Goicoechea, M | |
dc.contributor.author | Craxton, A | |
dc.contributor.author | Moraes de Vasconcelos, N | |
dc.contributor.author | Guppy, N | |
dc.contributor.author | Cheung, K-MJ | |
dc.contributor.author | Cundy, NJ | |
dc.contributor.author | Pierrat, O | |
dc.contributor.author | Brennan, A | |
dc.contributor.author | Roumeliotis, TI | |
dc.contributor.author | Benstead-Hume, G | |
dc.contributor.author | Alexander, J | |
dc.contributor.author | Muirhead, G | |
dc.contributor.author | Layzell, S | |
dc.contributor.author | Lyu, W | |
dc.contributor.author | Roulstone, V | |
dc.contributor.author | Allen, M | |
dc.contributor.author | Baldock, H | |
dc.contributor.author | Legrand, A | |
dc.contributor.author | Gabel, F | |
dc.contributor.author | Serrano-Aparicio, N | |
dc.contributor.author | Starling, C | |
dc.contributor.author | Guo, H | |
dc.contributor.author | Upton, J | |
dc.contributor.author | Gyrd-Hansen, M | |
dc.contributor.author | MacFarlane, M | |
dc.contributor.author | Seddon, B | |
dc.contributor.author | Raynaud, F | |
dc.contributor.author | Roxanis, I | |
dc.contributor.author | Harrington, K | |
dc.contributor.author | Haider, S | |
dc.contributor.author | Choudhary, JS | |
dc.contributor.author | Hoelder, S | |
dc.contributor.author | Tenev, T | |
dc.contributor.author | Meier, P | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2024-05-29T13:04:35Z | |
dc.date.available | 2024-05-29T13:04:35Z | |
dc.date.issued | 2024-05-15 | |
dc.identifier | S1074-7613(24)00230-9 | |
dc.identifier.citation | Immunity, 2024, | |
dc.identifier.issn | 1074-7613 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/6250 | |
dc.identifier.eissn | 1097-4180 | |
dc.identifier.eissn | 1097-4180 | |
dc.identifier.doi | 10.1016/j.immuni.2024.04.025 | |
dc.identifier.doi | 10.1016/j.immuni.2024.04.025 | |
dc.description.abstract | Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that coordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffold function mediates strong pro-survival signaling. Accordingly, cancer cells can hijack RIPK1 to block necroptosis and evade immune detection. We generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signaling hubs, accentuating the output of NF-κB, MAPK, and IFN signaling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. We further demonstrated that RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy by sensitizing cancer cells to treatment-induced TNF and interferons. This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies. | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | Elsevier BV | |
dc.relation.ispartof | Immunity | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | RIPK1 | |
dc.subject | TLR3 | |
dc.subject | TNF | |
dc.subject | anticancer immunity | |
dc.subject | cell death | |
dc.subject | immunotherapy | |
dc.subject | inflammation | |
dc.subject | interferon | |
dc.subject | necroptosis | |
dc.subject | radiotherapy | |
dc.title | A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2024-04-25 | |
dc.date.updated | 2024-05-28T20:23:43Z | |
rioxxterms.version | AM | |
rioxxterms.versionofrecord | 10.1016/j.immuni.2024.04.025 | |
rioxxterms.licenseref.startdate | 2024-05-15 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/38788712 | |
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/Cell Death and Immunity | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy | |
pubs.organisational-group | ICR/Students | |
pubs.organisational-group | ICR/Students/PhD and MPhil | |
pubs.organisational-group | ICR/Students/PhD and MPhil/20/21 Starting Cohort | |
pubs.organisational-group | ICR/ImmNet | |
pubs.publication-status | Published online | |
pubs.publisher-url | http://dx.doi.org/10.1016/j.immuni.2024.04.025 | |
icr.researchteam | Cell Death and Immunity | |
icr.researchteam | Targeted Therapy | |
dc.contributor.icrauthor | Mannion, Jonathan | |
dc.contributor.icrauthor | Harrington, Kevin | |
dc.contributor.icrauthor | Hoelder, Swen | |
dc.contributor.icrauthor | Tenev, Tencho | |
dc.contributor.icrauthor | Meier, Pascal | |
icr.provenance | Deposited by Prof Pascal Meier on 2024-05-28. Deposit type is initial. No. of files: 1. Files: Mannion et al.pdf | |