Mannion et al. developed a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated acute RIPK1 deletion primed TNFR1 and TLR3/4 pathways to overactivate NF-κB, MAPK, and IFN signaling, and simultaneously promoted RIPK3 activation and necroptosis induction. RIPK1 depletion sensitized cancer cells to radiation therapy-induced TNF and interferons, promoted immunogenic cell death, drove long-lasting antitumor immunity, and enhanced the immunostimulatory effects of radio- and immunotherapy.
Contributed by Shishir Pant
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-_B, 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.
Author Info: (1) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (2) The Breast Cancer Now Toby Robins Research Centre, The
Author Info: (1) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (2) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (3) Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK. (4) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (5) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (6) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (7) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (8) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (9) Division of Radiotherapy and Imaging, The Institute of Cancer Research, London SW3 6JB, UK. (10) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (11) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (12) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (13) MRC Toxicology Unit, University of Cambridge, Gleeson Building, Cambridge CB2 1QR, UK. (14) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (15) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (16) Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK. (17) Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK. (18) Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK. (19) Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK. (20) Functional Proteomics Group, The Institute of Cancer Research, London SW3 6JB, UK. (21) Functional Proteomics Group, The Institute of Cancer Research, London SW3 6JB, UK. (22) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (23) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (24) Institute of Immunity and Transplantation, University College London, London NW3 2PP, UK. (25) Department of Immunology and Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark. (26) Division of Radiotherapy and Imaging, The Institute of Cancer Research, London SW3 6JB, UK. (27) Biological Services Unit, The Institute of Cancer Research, London SW3 6JB, UK. (28) Biological Services Unit, The Institute of Cancer Research, London SW3 6JB, UK. (29) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (30) Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK. (31) Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK. (32) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (33) Department of Microbiology and Immunology, LSU Health Shreveport, Shreveport, LA, USA. (34) Department of Biological Sciences, Auburn University, Auburn, AL, USA. (35) Department of Immunology and Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark. (36) MRC Toxicology Unit, University of Cambridge, Gleeson Building, Cambridge CB2 1QR, UK. (37) Institute of Immunity and Transplantation, University College London, London NW3 2PP, UK. (38) Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK. (39) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (40) Division of Radiotherapy and Imaging, The Institute of Cancer Research, London SW3 6JB, UK. (41) The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK. (42) Functional Proteomics Group, The Institute of Cancer Research, London SW3 6JB, UK. (43) Centre for Cancer Drug Discovery at the Institute of Cancer Research, London SM2 5NG, UK. (44) 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. (45) 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.
