TY - JOUR
T1 - cFLIP suppression and DR5 activation sensitize senescent cancer cells to senolysis
AU - Wang, Liqin
AU - Jin, Haojie
AU - Jochems, Fleur
AU - Wang, Siying
AU - Lieftink, Cor
AU - Martinez, Isabel Mora
AU - de Conti, Giulia
AU - Edwards, Finn
AU - de Oliveira, Rodrigo Leite
AU - Schepers, Arnout
AU - Zhou, Yangyang
AU - Zheng, Jiaojiao
AU - Wu, Wei
AU - Zheng, Xingling
AU - Yuan, Shengxian
AU - Ling, Jing
AU - Jastrzebski, Kathy
AU - Santos Dias, Matheus Dos
AU - Song, Ji-Ying
AU - Celie, Patrick N. H.
AU - Yagita, Hideo
AU - Yao, Ming
AU - Zhou, Weiping
AU - Beijersbergen, Roderick L.
AU - Qin, Wenxin
AU - Bernards, René
N1 - Funding Information: We thank members of the Bernards laboratory and J. Borst and I. Verbrugge for helpful discussion and thoughtful feedback. This work was supported by the European Research Council as ERC-787925 (R.B.), 19-051-ASP from the Mark Foundation (R.B.), KWF-12539 from the Dutch Cancer Society (RL.B.), 81920108025, 82011530441 and 82073039 from the National Natural Science Foundation of China (H.J., W.Q. and R.B.) and 22XD1423100 from the program of Shanghai Academic/Technology Research Leader (H.J.). Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/11
Y1 - 2022/11
N2 - Senolytics, drugs that kill senescent cells, have been proposed to improve the response to pro-senescence cancer therapies; however, this remains challenging due to a lack of broadly acting senolytic drugs. Using CRISPR/Cas9-based genetic screens in different senescent cancer cell models, we identify loss of the death receptor inhibitor cFLIP as a common vulnerability of senescent cancer cells. Senescent cells are primed for apoptotic death by NF-κB-mediated upregulation of death receptor 5 (DR5) and its ligand TRAIL, but are protected from death by increased cFLIP expression. Activation of DR5 signaling by agonistic antibody, which can be enhanced further by suppression of cFLIP by BRD2 inhibition, leads to efficient killing of a variety of senescent cancer cells. Moreover, senescent cells sensitize adjacent non-senescent cells to killing by DR5 agonist through a bystander effect mediated by secretion of cytokines. We validate this ‘one-two punch’ cancer therapy by combining pro-senescence therapy with DR5 activation in different animal models.
AB - Senolytics, drugs that kill senescent cells, have been proposed to improve the response to pro-senescence cancer therapies; however, this remains challenging due to a lack of broadly acting senolytic drugs. Using CRISPR/Cas9-based genetic screens in different senescent cancer cell models, we identify loss of the death receptor inhibitor cFLIP as a common vulnerability of senescent cancer cells. Senescent cells are primed for apoptotic death by NF-κB-mediated upregulation of death receptor 5 (DR5) and its ligand TRAIL, but are protected from death by increased cFLIP expression. Activation of DR5 signaling by agonistic antibody, which can be enhanced further by suppression of cFLIP by BRD2 inhibition, leads to efficient killing of a variety of senescent cancer cells. Moreover, senescent cells sensitize adjacent non-senescent cells to killing by DR5 agonist through a bystander effect mediated by secretion of cytokines. We validate this ‘one-two punch’ cancer therapy by combining pro-senescence therapy with DR5 activation in different animal models.
UR - http://www.scopus.com/inward/record.url?scp=85142223578&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s43018-022-00462-2
DO - https://doi.org/10.1038/s43018-022-00462-2
M3 - Article
C2 - 36414711
SN - 2662-1347
VL - 3
SP - 1284
EP - 1299
JO - Nature Cancer
JF - Nature Cancer
IS - 11
ER -