Amazing stuff! Cancer is history (soon)!
"Scientists ... have made a breakthrough in understanding how cancer cells can evade the cell-killing effects of chemotherapy and enter a "zombie-like state," called premature senescence, that can attract the wound-healing properties of the immune system. ...
However, cancers can exploit these wound-healing capabilities for their own ends by masquerading as damaged tissue and tricking the immune system into helping malignant cells to divide and acquire extra oxygen and nutrients rather than killing them. ... how they switch on the wound-healing capabilities of the immune system is still poorly understood. ...
scientists ... have found that molecules called inhibitor of apoptosis proteins (IAPs) can enable tumors to escape the cell-killing effects of commonly used chemotherapeutic drugs. ...
found that IAPs functioned in this setting by neutralizing the cell-killing effects of molecules called "death receptors" that were switched on in response to DNA damage provoked by chemotherapy.
Furthermore, rather than simply allowing tumors to escape the cell-killing effects of chemotherapeutic drugs, IAPs enabled surviving tumor cells to enter a highly unusual zombie-like state called "premature senescence" that converts cells into coordinators of wound healing that can orchestrate a beneficial immune response and help tumors bounce back from chemotherapy. ...
found that senescent cells formed in response to chemotherapy are highly dependent on IAPs for their continued survival. Accordingly, compounds that neutralized IAPs (called IAP antagonists) selectively eliminated senescent cells by reactivating the death receptor self-destruct program within these cells. ..."
From the 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."
Death receptors regulate entry to therapy-induced senescence and orchestrate addiction to IAPs (open access)
Fig. 1. cFLIPL and Caspase-8 regulate entry to DNA damage–induced senescence.
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