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

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

  • Immunity. 2024 May 15:S1074-7613(24)00230-9. doi: 10.1016/j.immuni.2024.04.025.
Jonathan Mannion 1,  Valentina Gifford 1,  Benjamin Bellenie 2,  Winnie Fernando 1,  Laura Ramos Garcia 1,  Rebecca Wilson 1,  Sidonie Wicky John 1,  Savita Udainiya 1,  Emmanuel C Patin 3,  Crescens Tiu 1,  Angel Smith 1,  Maria Goicoechea 1,  Andrew Craxton 4,  Nathalia Moraes de Vasconcelos 1,  Naomi Guppy 1,  Kwai-Ming J Cheung 2,  Nicholas J Cundy 2,  Olivier Pierrat 2,  Alfie Brennan 2,  Theodoros I Roumeliotis 5,  Graeme Benstead-Hume 5,  John Alexander 1,  Gareth Muirhead 1,  Scott Layzell 6,  Wenxin Lyu 7,  Victoria Roulstone 3,  Mark Allen 8,  Holly Baldock 8,  Arnaud Legrand 1,  Florian Gabel 2,  Natalia Serrano-Aparicio 2,  Chris Starling 1,  Hongyan Guo 9,  Jason Upton 10,  Mads Gyrd-Hansen 7,  Marion MacFarlane 4,  Benedict Seddon 6,  Florence Raynaud 2,  Ioannis Roxanis 1,  Kevin Harrington 3,  Syed Haider 1,  Jyoti S Choudhary 5,  Swen Hoelder 2,  Tencho Tenev 11,  Pascal Meier 12
Affiliations

Affiliations

  • 1 The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.
  • 2 Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK.
  • 3 Division of Radiotherapy and Imaging, The Institute of Cancer Research, London SW3 6JB, UK.
  • 4 MRC Toxicology Unit, University of Cambridge, Gleeson Building, Cambridge CB2 1QR, UK.
  • 5 Functional Proteomics Group, The Institute of Cancer Research, London SW3 6JB, UK.
  • 6 Institute of Immunity and Transplantation, University College London, London NW3 2PP, UK.
  • 7 Department of Immunology and Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark.
  • 8 Biological Services Unit, The Institute of Cancer Research, London SW3 6JB, UK.
  • 9 Department of Microbiology and Immunology, LSU Health Shreveport, Shreveport, LA, USA.
  • 10 Department of Biological Sciences, Auburn University, Auburn, AL, USA.
  • 11 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.
  • 12 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.
PMID: 38788712 DOI: 10.1016/j.immuni.2024.04.025
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.

Keywords

RIPK1; TLR3; TNF; anticancer immunity; cell death; immunotherapy; inflammation; interferon; necroptosis; radiotherapy.

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