GSE191255
RNA seq on NEO2734, CFI-400945 or SASP treated cells
Senolytics, drugs that kill senescent cells, have been proposed to improve the response to pro-senescence cancer therapies. However, lack of broadly acting senolytic drugs remains a challenge. Using inducible CRISPR/Cas9-based genetic screens in different senescent cancer cell models, we identify here loss of the death receptor inhibitor cFLIP as a universal vulnerability of senescent cancer cells. Senescent cancer cells are primed for apoptotic death by NF-kB-mediated upregulation of death receptor DR5 and its ligand TRAIL but are protected from death by increased cFLIP. Activation of DR5 signaling by agonistic antibody, which can be enhanced further by suppression of cFLIP by BRD2 inhibition, leads to efficient killing of all senescent cancer cells tested. We validate this ?one-two punch? cancer therapy by combining pro-senescence therapy with DR5 activation in different animal models. Overall design: The cancer cells (PC9, SK-Hep1 or A549) were treated with the indicated drugs or conditional medium for 1 week, and then RNA were isolated for analysis Transcriptomic analysis of treatment on different cell models, see the changes on gene expression upon the treatments