Death receptors regulate entry to therapy-induced senescence and orchestrate addiction to IAPs
8 affiliations
- 1Molecular Cell Biology Laboratory, Dept. of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
- 2Institute for Molecular Immunology, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.
- 3Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia.
- 4School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia.
- 5BioFrontiers Institute, University of Colorado, Boulder, CO 80303, USA.
- 6La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086 Australia.
- 7Neurovascular Genetics Unit, Dept. of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
- 8Dept. of Clinical Medicine and Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
Abstract
Cytotoxic chemotherapy typically results in the elimination of a fraction of the tumor with surviving cells entering a state of persistence or premature replicative senescence that can lead to recurrence. Here, we show that therapy-induced senescence is associated with robust up-regulation of Fas and/or TRAIL-R2/DR5 death receptors in vitro and in vivo. The latter receptors restricted entry to senescence and exerted selective pressure on senescent cells through promoting assembly of proapoptotic receptor-interacting protein kinase 1 (RIPK1)/Fas-associated death domain protein (FADD)/Caspase-8 "FADDosome" complexes, restrained by cFLIPL. Accordingly, deletion of CASP-8 robustly enhanced entry to senescence and prolonged the life span of senescent cells. cIAP-2, which inhibits death receptor-driven cell death, was also up-regulated in senescent cells, and deletion of IAPs suppressed entry to senescence. Consistent with this, small-molecule IAP antagonists exhibited potent senolytic activity through enhancing death receptor-initiated Caspase-8 activation. Thus, death receptor-driven assembly of RIPK1/FADD/Caspase-8 complexes in senescent cells orchestrates addiction to IAPs that can be exploited by IAP antagonists.
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BibTeX
@article{gunay2026death,
title = {{Death receptors regulate entry to therapy-induced senescence and orchestrate addiction to IAPs}},
author = {Gokhan Gunay and Seren Hamsici and Vaishnavi Venugopalan and Aoife Costigan and Melanie Fritsch and Aislinn Gallagher Aldave and Anne Huber and Brianna Fernandez and Hande Efe-Cicek and Pavel Davidovich and Pavitha Parathan and Akash Srivaths and Natalie Hudson and Eleanor Noone and Jeffrey O’Callaghan and Lisa A. Mielke and Sarah L. Doyle and Sabrina L. Spencer and Matthew Campbell and Conor J. Kearney and Hamid Kashkar and Seamus J. Martin},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aed4541},
url = {https://www.science.org/doi/10.1126/sciadv.aed4541},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Death receptors regulate entry to therapy-induced senescence and orchestrate addiction to IAPs
AU - Gokhan Gunay
AU - Seren Hamsici
AU - Vaishnavi Venugopalan
AU - Aoife Costigan
AU - Melanie Fritsch
AU - Aislinn Gallagher Aldave
AU - Anne Huber
AU - Brianna Fernandez
AU - Hande Efe-Cicek
AU - Pavel Davidovich
AU - Pavitha Parathan
AU - Akash Srivaths
AU - Natalie Hudson
AU - Eleanor Noone
AU - Jeffrey O’Callaghan
AU - Lisa A. Mielke
AU - Sarah L. Doyle
AU - Sabrina L. Spencer
AU - Matthew Campbell
AU - Conor J. Kearney
AU - Hamid Kashkar
AU - Seamus J. Martin
PY - 2026
DA - 2026/10/23
JO - Science Advances
DO - 10.1126/sciadv.aed4541
UR - https://www.science.org/doi/10.1126/sciadv.aed4541
AB - Cytotoxic chemotherapy typically results in the elimination of a fraction of the tumor with surviving cells entering a state of persistence or premature replicative senescence that can lead to recurrence. Here, we show that therapy-induced senescence is associated with robust up-regulation of Fas and/or TRAIL-R2/DR5 death receptors in vitro and in vivo. The latter receptors restricted entry to senescence and exerted selective pressure on senescent cells through promoting assembly of proapoptotic receptor-interacting protein kinase 1 (RIPK1)/Fas-associated death domain protein (FADD)/Caspase-8 "FADDosome" complexes, restrained by cFLIPL. Accordingly, deletion of CASP-8 robustly enhanced entry to senescence and prolonged the life span of senescent cells. cIAP-2, which inhibits death receptor-driven cell death, was also up-regulated in senescent cells, and deletion of IAPs suppressed entry to senescence. Consistent with this, small-molecule IAP antagonists exhibited potent senolytic activity through enhancing death receptor-initiated Caspase-8 activation. Thus, death receptor-driven assembly of RIPK1/FADD/Caspase-8 complexes in senescent cells orchestrates addiction to IAPs that can be exploited by IAP antagonists.
SN - 2375-2548
ER -