A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells

Masahiro Wakita, Akiko Takahashi, Osamu Sano, Tze Mun Loo, Yoshinori Imai, Megumi Narukawa, Hidehisa Iwata, Tatsuyuki Matsudaira, Shimpei Kawamoto, Naoko Ohtani, Tamotsu Yoshimori and Eiji Hara ()
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Masahiro Wakita: Osaka University
Akiko Takahashi: Cancer Institute, Japanese Foundation for Cancer Research
Osamu Sano: Takeda Pharmaceutical Company Ltd.
Tze Mun Loo: Cancer Institute, Japanese Foundation for Cancer Research
Yoshinori Imai: Cancer Institute, Japanese Foundation for Cancer Research
Megumi Narukawa: Osaka University
Hidehisa Iwata: Takeda Pharmaceutical Company Ltd.
Tatsuyuki Matsudaira: Osaka University
Shimpei Kawamoto: Osaka University
Naoko Ohtani: Osaka City University
Tamotsu Yoshimori: Osaka University
Eiji Hara: Osaka University

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Although cellular senescence acts primarily as a tumour suppression mechanism, the accumulation of senescent cells in vivo eventually exerts deleterious side effects through inflammatory/tumour-promoting factor secretion. Thus, the development of new drugs that cause the specific elimination of senescent cells, termed senolysis, is anticipated. Here, by an unbiased high-throughput screening of chemical compounds and a bio-functional analysis, we identify BET family protein degrader (BETd) as a promising senolytic drug. BETd provokes senolysis through two independent but integrated pathways; the attenuation of non-homologous end joining (NHEJ), and the up-regulation of autophagic gene expression. BETd treatment eliminates senescent hepatic stellate cells in obese mouse livers, accompanied by the reduction of liver cancer development. Furthermore, the elimination of chemotherapy-induced senescent cells by BETd increases the efficacy of chemotherapy against xenograft tumours in immunocompromised mice. These results reveal the vulnerability of senescent cells and open up possibilities for its control.

Date: 2020
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DOI: 10.1038/s41467-020-15719-6

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