دورية أكاديمية
أعرض في EDS

A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death.

التفاصيل البيبلوغرافية
العنوان: A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death.
المؤلفون: Mannion J; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Gifford V; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Bellenie B; Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK., Fernando W; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Ramos Garcia L; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Wilson R; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., John SW; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Udainiya S; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Patin EC; Division of Radiotherapy and Imaging, The Institute of Cancer Research, London SW3 6JB, UK., Tiu C; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Smith A; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Goicoechea M; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Craxton A; MRC Toxicology Unit, University of Cambridge, Gleeson Building, Cambridge CB2 1QR, UK., Moraes de Vasconcelos N; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Guppy N; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Cheung KJ; Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK., Cundy NJ; Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK., Pierrat O; Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK., Brennan A; Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK., Roumeliotis TI; Functional Proteomics Group, The Institute of Cancer Research, London SW3 6JB, UK., Benstead-Hume G; Functional Proteomics Group, The Institute of Cancer Research, London SW3 6JB, UK., Alexander J; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Muirhead G; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Layzell S; Institute of Immunity and Transplantation, University College London, London NW3 2PP, UK., Lyu W; Department of Immunology and Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark., Roulstone V; Division of Radiotherapy and Imaging, The Institute of Cancer Research, London SW3 6JB, UK., Allen M; Biological Services Unit, The Institute of Cancer Research, London SW3 6JB, UK., Baldock H; Biological Services Unit, The Institute of Cancer Research, London SW3 6JB, UK., Legrand A; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Gabel F; Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK., Serrano-Aparicio N; Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK., Starling C; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Guo H; Department of Microbiology and Immunology, LSU Health Shreveport, Shreveport, LA, USA., Upton J; Department of Biological Sciences, Auburn University, Auburn, AL, USA., Gyrd-Hansen M; Department of Immunology and Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark., MacFarlane M; MRC Toxicology Unit, University of Cambridge, Gleeson Building, Cambridge CB2 1QR, UK., Seddon B; Institute of Immunity and Transplantation, University College London, London NW3 2PP, UK., Raynaud F; Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK., Roxanis I; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Harrington K; Division of Radiotherapy and Imaging, The Institute of Cancer Research, London SW3 6JB, UK., Haider S; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Choudhary JS; Functional Proteomics Group, The Institute of Cancer Research, London SW3 6JB, UK., Hoelder S; Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK., Tenev T; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. Electronic address: tencho.tenev@icr.ac.uk., Meier P; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. Electronic address: pmeier@icr.ac.uk.
المصدر: Immunity [Immunity] 2024 Jul 09; Vol. 57 (7), pp. 1514-1532.e15. Date of Electronic Publication: 2024 May 23.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 9432918 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4180 (Electronic) Linking ISSN: 10747613 NLM ISO Abbreviation: Immunity Subsets: MEDLINE
أسماء مطبوعة: Publication: Cambridge, MA : Cell Press
Original Publication: Cambridge, Mass. : Cell Press, c1994-
مواضيع طبية MeSH: Receptor-Interacting Protein Serine-Threonine Kinases*/metabolism , Proteolysis*/drug effects , Signal Transduction*/drug effects , Immunogenic Cell Death*/drug effects, Humans ; Animals ; Mice ; Cell Line, Tumor ; Necroptosis/drug effects ; Necroptosis/immunology ; Neoplasms/immunology ; Neoplasms/drug therapy ; Mice, Inbred C57BL ; Antineoplastic Agents/pharmacology ; Immunotherapy/methods
مستخلص: 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.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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معلومات مُعتمدة: R21 AI175590 United States AI NIAID NIH HHS
فهرسة مساهمة: Keywords: RIPK1; TLR3; TNF; anticancer immunity; cell death; immunotherapy; inflammation; interferon; necroptosis; radiotherapy
المشرفين على المادة: EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases)
EC 2.7.11.1 (RIPK1 protein, human)
EC 2.7.11.1 (Ripk1 protein, mouse)
0 (Antineoplastic Agents)
تواريخ الأحداث: Date Created: 20240524 Date Completed: 20240710 Latest Revision: 20240712
رمز التحديث: 20240712
مُعرف محوري في PubMed: PMC11236506
DOI: 10.1016/j.immuni.2024.04.025
PMID: 38788712
قاعدة البيانات: MEDLINE
الوصف
تدمد:1097-4180
DOI:10.1016/j.immuni.2024.04.025