 Inducing and exploiting vulnerabilities for the treatment of liver cancerCun Wang,
Serena Vegna,
Haojie Jin,
Bente Benedict,
Cor Lieftink,
Christel Ramirez,
Rodrigo Leite Oliveira,
Ben Morris,
Jules Gadiot,
Wei Wang,
Aimée Chatinier,
Liqin Wang,
Dongmei Gao,
Bastiaan Evers,
Guangzhi Jin,
Zheng Xue,
Arnout Schepers,
Fleur Jochems,
Antonio Mulero Sanchez,
Sara Mainardi,
Hein Riele,
Roderick L. Beijersbergen,
Wenxin Qin (),
Leila Akkari () and
René Bernards ()
Nature, 2019, vol. 574, issue 7777, 268-272 Abstract: Abstract Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies1,2; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients with hepatocellular carcinoma3. The induction of senescence may represent a strategy for the treatment of cancer, especially when combined with a second drug that selectively eliminates senescent cancer cells (senolysis)4,5. Here, using a kinome-focused genetic screen, we show that pharmacological inhibition of the DNA-replication kinase CDC7 induces senescence selectively in liver cancer cells with mutations in TP53. A follow-up chemical screen identified the antidepressant sertraline as an agent that kills hepatocellular carcinoma cells that have been rendered senescent by inhibition of CDC7. Sertraline suppressed mTOR signalling, and selective drugs that target this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signalling after its inhibition6 is blocked in cells that have been treated with a CDC7 inhibitor, which leads to the sustained inhibition of mTOR and cell death. Using multiple in vivo mouse models of liver cancer, we show that treatment with combined inhibition of of CDC7 and mTOR results in a marked reduction of tumour growth. Our data indicate that exploiting an induced vulnerability could be an effective treatment for liver cancer. Date: 2019 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:574:y:2019:i:7777:d:10.1038_s41586-019-1607-3 Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-019-1607-3 Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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