Authors
Gokhan Gunay, Seren Hamsici, Vaishnavi Venugopalan, Aoife Costigan, Melanie Fritsch, Aislinn Gallagher Aldave, Anne Huber, Brianna Fernandez, Hande Efe-Cicek, Pavel Davidovich, Pavitha Parathan, Akash Srivaths, Natalie Hudson, Eleanor Noone, Jeffrey O'Callaghan, Lisa A Mielke, Sarah L Doyle, Sabrina L Spencer, Matthew Campbell, Conor J Kearney, Hamid Kashkar, Seamus J Martin
Published in
Science advances. Volume 12. Issue 43. Pages eaed4541. Oct 23, 2026. Epub Oct 23, 2026.
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.
PMID:
42912996
Bibliographic data and abstract were imported from PubMed on 24 Oct 2026.
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