Inducing and exploiting vulnerabilities for the treatment of liver cancer.

Abstract

Liver cancer remains difficult to treat due to a paucity of drugs that target critical dependencies1,2 and broad spectrum kinase inhibitors like sorafenib provide only modest benefit to hepatocellular carcinoma (HCC) patients3. Induction of senescence may represent a promising strategy for the treatment of cancer, especially when such pro-senescence therapy is combined with a second drug that selectively eliminates senescent cancer cells (senolysis)4,5. Through a kinome-focused genetic screen, we report here that pharmacological inhibition of the DNA replication kinase CDC7 induces senescence selectively in TP53 mutant liver cancer cells. A follow-up chemical screen identified the anti-depressant sertraline as an agent that kills HCC cells rendered senescent by CDC7 inhibition. Sertraline supressed mTOR signalling, and selective drugs targeting this pathway were highly effective in causing apoptotic cell death of CDC7 inhibitor-treated HCC cells. Mechanistically, we report that the feedback re-activation of mTOR signalling following its inhibition6 is blocked in CDC7-inhibitor treated cells, leading to sustained mTOR inhibition and cell death. Using multiple in vivo liver cancer models, we show that combination of CDC7 and mTOR inhibitors results in dramatic tumour growth inhibition. More generally, our data indicate that exploiting an induced vulnerability could be an effective treatment of liver cancer.