Death receptors regulate entry to therapy-induced senescence and orchestrate addiction to IAPs.

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.