1. Academic Validation
  2. 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: [email protected].
  • 12 The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. Electronic address: [email protected].
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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