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
  • 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].
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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