A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death.
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Authors
Mannion, J
Gifford, V
Bellenie, B
Fernando, W
Ramos Garcia, L
Wilson, R
John, SW
Udainiya, S
Patin, EC
Tiu, C
Smith, A
Goicoechea, M
Craxton, A
Moraes de Vasconcelos, N
Guppy, N
Cheung, K-MJ
Cundy, NJ
Pierrat, O
Brennan, A
Roumeliotis, TI
Benstead-Hume, G
Alexander, J
Muirhead, G
Layzell, S
Lyu, W
Roulstone, V
Allen, M
Baldock, H
Legrand, A
Gabel, F
Serrano-Aparicio, N
Starling, C
Guo, H
Upton, J
Gyrd-Hansen, M
MacFarlane, M
Seddon, B
Raynaud, F
Roxanis, I
Harrington, K
Haider, S
Choudhary, JS
Hoelder, S
Tenev, T
Meier, P
Gifford, V
Bellenie, B
Fernando, W
Ramos Garcia, L
Wilson, R
John, SW
Udainiya, S
Patin, EC
Tiu, C
Smith, A
Goicoechea, M
Craxton, A
Moraes de Vasconcelos, N
Guppy, N
Cheung, K-MJ
Cundy, NJ
Pierrat, O
Brennan, A
Roumeliotis, TI
Benstead-Hume, G
Alexander, J
Muirhead, G
Layzell, S
Lyu, W
Roulstone, V
Allen, M
Baldock, H
Legrand, A
Gabel, F
Serrano-Aparicio, N
Starling, C
Guo, H
Upton, J
Gyrd-Hansen, M
MacFarlane, M
Seddon, B
Raynaud, F
Roxanis, I
Harrington, K
Haider, S
Choudhary, JS
Hoelder, S
Tenev, T
Meier, P
Document Type
Journal Article
Date
2024-07-09
Date Accepted
2024-04-25
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.
Citation
Immunity, 2024,
Source Title
Immunity
Publisher
CELL PRESS
ISSN
1074-7613
eISSN
1097-4180
1097-4180
1097-4180
Collections
Research Team
Cell Death and Immunity
Targeted Therapy
Targeted Therapy