A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Standard

A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death. / Mannion, Jonathan; Gifford, Valentina; Bellenie, Benjamin; Fernando, Winnie; Ramos Garcia, Laura; Wilson, Rebecca; John, Sidonie Wicky; Udainiya, Savita; Patin, Emmanuel C.; Tiu, Crescens; Smith, Angel; Goicoechea, Maria; Craxton, Andrew; Moraes de Vasconcelos, Nathalia; Guppy, Naomi; Cheung, Kwai Ming J.; Cundy, Nicholas J.; Pierrat, Olivier; Brennan, Alfie; Roumeliotis, Theodoros I.; Benstead-Hume, Graeme; Alexander, John; Muirhead, Gareth; Layzell, Scott; Lyu, Wenxin; Roulstone, Victoria; Allen, Mark; Baldock, Holly; Legrand, Arnaud; Gabel, Florian; Serrano-Aparicio, Natalia; Starling, Chris; Guo, Hongyan; Upton, Jason; Gyrd-Hansen, Mads; MacFarlane, Marion; Seddon, Benedict; Raynaud, Florence; Roxanis, Ioannis; Harrington, Kevin; Haider, Syed; Choudhary, Jyoti S.; Hoelder, Swen; Tenev, Tencho; Meier, Pascal.

I: Immunity, 2024.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

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, KMJ, 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 2024, 'A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death', Immunity. https://doi.org/10.1016/j.immuni.2024.04.025

APA

Mannion, J., Gifford, V., Bellenie, B., Fernando, W., Ramos Garcia, L., Wilson, R., John, S. W., Udainiya, S., Patin, E. C., Tiu, C., Smith, A., Goicoechea, M., Craxton, A., Moraes de Vasconcelos, N., Guppy, N., Cheung, K. M. J., Cundy, N. J., Pierrat, O., Brennan, A., ... Meier, P. (2024). A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death. Immunity. https://doi.org/10.1016/j.immuni.2024.04.025

Vancouver

Mannion J, Gifford V, Bellenie B, Fernando W, Ramos Garcia L, Wilson R o.a. A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death. Immunity. 2024. https://doi.org/10.1016/j.immuni.2024.04.025

Author

Mannion, Jonathan ; Gifford, Valentina ; Bellenie, Benjamin ; Fernando, Winnie ; Ramos Garcia, Laura ; Wilson, Rebecca ; John, Sidonie Wicky ; Udainiya, Savita ; Patin, Emmanuel C. ; Tiu, Crescens ; Smith, Angel ; Goicoechea, Maria ; Craxton, Andrew ; Moraes de Vasconcelos, Nathalia ; Guppy, Naomi ; Cheung, Kwai Ming J. ; Cundy, Nicholas J. ; Pierrat, Olivier ; Brennan, Alfie ; Roumeliotis, Theodoros I. ; Benstead-Hume, Graeme ; Alexander, John ; Muirhead, Gareth ; Layzell, Scott ; Lyu, Wenxin ; Roulstone, Victoria ; Allen, Mark ; Baldock, Holly ; Legrand, Arnaud ; Gabel, Florian ; Serrano-Aparicio, Natalia ; Starling, Chris ; Guo, Hongyan ; Upton, Jason ; Gyrd-Hansen, Mads ; MacFarlane, Marion ; Seddon, Benedict ; Raynaud, Florence ; Roxanis, Ioannis ; Harrington, Kevin ; Haider, Syed ; Choudhary, Jyoti S. ; Hoelder, Swen ; Tenev, Tencho ; Meier, Pascal. / A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death. I: Immunity. 2024.

Bibtex

@article{db10cb4c16044a2081cd6453277bbf7d,
title = "A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death",
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 = "anticancer immunity, cell death, immunotherapy, inflammation, interferon, necroptosis, radiotherapy, RIPK1, TLR3, TNF",
author = "Jonathan Mannion and Valentina Gifford and Benjamin Bellenie and Winnie Fernando and {Ramos Garcia}, Laura and Rebecca Wilson and John, {Sidonie Wicky} and Savita Udainiya and Patin, {Emmanuel C.} and Crescens Tiu and Angel Smith and Maria Goicoechea and Andrew Craxton and {Moraes de Vasconcelos}, Nathalia and Naomi Guppy and Cheung, {Kwai Ming J.} and Cundy, {Nicholas J.} and Olivier Pierrat and Alfie Brennan and Roumeliotis, {Theodoros I.} and Graeme Benstead-Hume and John Alexander and Gareth Muirhead and Scott Layzell and Wenxin Lyu and Victoria Roulstone and Mark Allen and Holly Baldock and Arnaud Legrand and Florian Gabel and Natalia Serrano-Aparicio and Chris Starling and Hongyan Guo and Jason Upton and Mads Gyrd-Hansen and Marion MacFarlane and Benedict Seddon and Florence Raynaud and Ioannis Roxanis and Kevin Harrington and Syed Haider and Choudhary, {Jyoti S.} and Swen Hoelder and Tencho Tenev and Pascal Meier",
note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",
year = "2024",
doi = "10.1016/j.immuni.2024.04.025",
language = "English",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",

}

RIS

TY - JOUR

T1 - A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death

AU - Mannion, Jonathan

AU - Gifford, Valentina

AU - Bellenie, Benjamin

AU - Fernando, Winnie

AU - Ramos Garcia, Laura

AU - Wilson, Rebecca

AU - John, Sidonie Wicky

AU - Udainiya, Savita

AU - Patin, Emmanuel C.

AU - Tiu, Crescens

AU - Smith, Angel

AU - Goicoechea, Maria

AU - Craxton, Andrew

AU - Moraes de Vasconcelos, Nathalia

AU - Guppy, Naomi

AU - Cheung, Kwai Ming J.

AU - Cundy, Nicholas J.

AU - Pierrat, Olivier

AU - Brennan, Alfie

AU - Roumeliotis, Theodoros I.

AU - Benstead-Hume, Graeme

AU - Alexander, John

AU - Muirhead, Gareth

AU - Layzell, Scott

AU - Lyu, Wenxin

AU - Roulstone, Victoria

AU - Allen, Mark

AU - Baldock, Holly

AU - Legrand, Arnaud

AU - Gabel, Florian

AU - Serrano-Aparicio, Natalia

AU - Starling, Chris

AU - Guo, Hongyan

AU - Upton, Jason

AU - Gyrd-Hansen, Mads

AU - MacFarlane, Marion

AU - Seddon, Benedict

AU - Raynaud, Florence

AU - Roxanis, Ioannis

AU - Harrington, Kevin

AU - Haider, Syed

AU - Choudhary, Jyoti S.

AU - Hoelder, Swen

AU - Tenev, Tencho

AU - Meier, Pascal

N1 - Publisher Copyright: © 2024 The Author(s)

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

KW - anticancer immunity

KW - cell death

KW - immunotherapy

KW - inflammation

KW - interferon

KW - necroptosis

KW - radiotherapy

KW - RIPK1

KW - TLR3

KW - TNF

U2 - 10.1016/j.immuni.2024.04.025

DO - 10.1016/j.immuni.2024.04.025

M3 - Journal article

C2 - 38788712

AN - SCOPUS:85195286501

JO - Immunity

JF - Immunity

SN - 1074-7613

ER -

ID: 395386314