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Published on: November 9, 2020
A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death
Jonathan Mannion1, Valentina Gifford1, Benjamin Bellenie2
1The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.
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.
Insights
Targeting Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) with PROTACs degrades the kinase, enhancing cancer cell death and immune response. This approach improves radio- and immunotherapy effectiveness, leading to durable antitumor immunity.
Area of Science:
- Molecular Biology
- Immunology
- Oncology
Background:
- Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a key regulator of cell survival, inflammation, and cell death.
- Cancer cells exploit RIPK1's scaffold function to resist necroptosis and immune surveillance.
- Targeting RIPK1 offers a potential strategy to enhance cancer therapies.
Purpose of the Study:
- To investigate the therapeutic potential of selectively degrading RIPK1 using a proteolysis-targeting chimera (PROTAC).
- To elucidate the downstream signaling effects of RIPK1 depletion on cell death pathways and immune signaling.
- To evaluate the efficacy of RIPK1 degradation in combination with radio- and immunotherapy.
Main Methods:
- Generation of a small-molecule PROTAC for selective RIPK1 degradation in human and murine cells.
- Analysis of RIPK1 depletion effects on TNFR1, TLR3/4, NF-κB, MAPK, and IFN signaling pathways.
- Assessment of RIPK1 degradation's impact on RIPK3 activation, necroptosis, and immunogenic cell death (ICD).
- Evaluation of combined RIPK1 degradation with radio- and immunotherapy in preclinical cancer models.
Main Results:
- PROTAC-mediated RIPK1 depletion deregulated key signaling hubs and enhanced NF-κB, MAPK, and IFN output.
- RIPK1 degradation promoted RIPK3 activation and induced necroptosis.
- Combined treatment sensitized cancer cells to TNF and interferons, promoting ICD and antitumor immunity.
- RIPK1 targeting via PROTACs led to durable treatment responses in preclinical models.
Conclusions:
- Selective RIPK1 degradation using PROTACs effectively triggers cell death and enhances anticancer immune responses.
- This approach overcomes resistance to radio- and immunotherapy by promoting ICD.
- Targeting RIPK1 with PROTACs represents a promising strategy to improve the efficacy of existing cancer therapies and overcome treatment resistance.
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