A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Immunity |
| ISSN | 1074-7613 |
| DOI | |
| Status | E-pub ahead of print - 2024 |
Bibliografisk note
Funding Information:
The authors are indebted to Clare Isacke, John Silke, Henning Walczak, Geert van Loo, Ulrich Maurer, B.C. Bornhauser, John Caldwell, Angela Hayes, Kai Betteridge, Queenie Lai, Ross Scrimgeour, Jin Wang, Daniel Glynn, Philip Clarke, James Krupa, Tom Pesnot, Peter John-Baptiste, Steven Lumbard, and the ICR Flow Cytometry Core Facility, who provided support and helpful discussions. Zbp1\u2212/\u2212, Trif\u2212/\u2212, and Trif\u2212/\u2212Zbp1\u2212/\u2212 BMDMs and LFs were kind gifts from Manolis Pasparakis. The Guo lab is supported by NIH-R21-R21AI175590. The Meier lab is funded by Breast Cancer Now (CTR-QR14-007) and CRUK (C26866/A24399 and CRM089X). We acknowledge NHS funding to the NIHR Biomedical Research Centre. P.M. T.T. and B.B. conceived the study, and J.M. P.M. and T.T. designed the research, wrote the paper, and generated the figures. J.M. designed, performed, and analyzed experiments in Figures 1, 2, 3, 4, 5, 6, and S1\u2013S7. T.T. designed, performed, and analyzed experiments in Figures 3, 4, 7, S1, S3, S6, and S7. P.M. and T.T. supervised the study. A.B. designed R1-ICR-3, and B.B. designed R1-ICR-5, -6, and -7. B.B. A.B. K.-M.J.C. N.J.C. O.P. F.R. and F.G. participated in the development of all RIPK1-PROTACs. B.B. and S. Hoelder supervised the RIPK1-PROTAC development. V.G. performed radiation experiments and experiments shown in Figures 2B, 5A, S1A, S1B, S3A, S3O, S7H, and S7I. W.F. performed all in vivo experiments. C.T. M.A. H.B. L.R.G. R.W. S.W.J. A.S. N.M.d.V. S.L. W.L. V.R. H.G. J.U. A.L. S.U. T.I.R. G.B.-H. E.C.P. A.C. N.G. C.S. S. Haider, J.A. N.S.-A. and G.M. performed diverse in vitro experiments. J.S.C. S. Hoelder, S. Haider, M.M. I.R. and K.H. supervised specific aspects of the study. B.B. S. Haider, V.G. W.F. R.W. S.W.J. A.S. and M.G. provided comments on the manuscript. The authors declare no competing interests.
Funding Information:
The authors are indebted to Clare Isacke, John Silke, Henning Walczak, Geert van Loo, Ulrich Maurer, B.C. Bornhauser, John Caldwell, Angela Hayes, Kai Betteridge, Queenie Lai, Ross Scrimgeour, Jin Wang, Daniel Glynn, Philip Clarke, James Krupa, Tom Pesnot, Peter John-Baptiste, Steven Lumbard, and the ICR Flow Cytometry Core Facility, who provided support and helpful discussions. Zbp1 \u2212/\u2212 , Trif \u2212/\u2212 , and Trif \u2212/\u2212 Zbp1 \u2212/\u2212 BMDMs and LF were kind gifts from Manolis Pasparakis. The Guo lab is supported by NIH - R21-R21AI175590 . The Meier lab is funded by Breast Cancer Now ( CTR-QR14-007 ) and CRUK ( C26866/A24399 and CRM089X ). We acknowledge NHS funding to the NIHR Biomedical Research Centre.
Publisher Copyright:
© 2024 The Author(s)
ID: 395386314