cFLIP suppression and DR5 activation sensitize senescent cancer cells to senolysis

Targeting of vulnerabilities of drug-tolerant persisters identified through functional genetics delays tumor relapse

“…Previously, our group reported that the inhibitor of extrinsic apoptosis signaling cFLIP is a vulnerability of senescent cancer cells and that the DR5 agonist conatumumab is a broadly acting senolytic agent. 18 However, in the context of persister cancer cells, the overexpression of cFLIP did not have an effect on the emergence of DTPs and could only partially rescue the killing of DTEPs by BET inhibitors ( Figures S9 D and S9E). Moreover, alisertib-induced senescent cancer cells are more vulnerable to conatumumab as compared to persisters ( Figure S9 F).…”

“…To complement the small-molecule screen and to identify genes essential for the survival of persisters, we performed a loss-of-function genetic screen using the doxycycline-inducible CRISPR-Cas9 vector system in PC9-SS cells. 18 Due to the rareness of persisters and their consequential small numbers, we choose to use a kinome-scale library for this screen. In short, we established PC9-SS cells stably expressing doxycycline-inducible Cas9 (PC9-SS-iCAS9) ( Figures S2 A–S2C).…”

Metochalcone induces senescence-associated secretory phenotype via JAK2/STAT3 pathway in breast cancer

“…Furthermore, the concept of “one-two punch” cancer therapy, combining pro-senescence therapy and senolytic therapy, has been considered an emerging and promising strategy to avoid paracrine and pro-oncogenic effects and to control neoplasia. This strategy has been realized in two programs: transformation of proliferating cells into senescent cells with pro-senescence treatment, followed by senolytic treatment to clean senescent cells [ 35 ]. Classically, SASP is induced and regulated through several pathways both in transcriptional and post-transcriptional modulation, such as NF-κB, JAK2/STAT3 signaling axis [ 34 ].…”

cFLIPL alleviates myocardial ischemia‐reperfusion injury by regulating pyroptosis

“…cFLIP is found in various organisms, such as viruses, eukaryotes, and mammals, and is expressed in multiple tissues, including the heart, skeletal muscle, lymphoid tissue, and kidneys (Lee et al, 2022). Recent studies have shown that the occurrence and progression of inflammation, tumors, cardiovascular diseases, and autoimmune diseases are closely related to the expression of cFLIP (Liu et al, 2021; Salvesen & Walsh, 2014; Suk et al, 2021; Wang et al, 2022). cFLIP contains at least 13 exons and co‐localizes with caspase‐8 and Caspase 10 genes on human chromosome 2q33‐34 .…”