Inducing and exploiting vulnerabilities for the treatment of liver cancer
Open accessAbstract
Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies 1,2; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients with hepatocellular carcinoma 3. 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 inhibition 6 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.
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Senescence induction by inhibition of DNA replication kinase CDC7 paired with a senolytic that disrupts mTOR signaling induces apoptosis in senescent human liver cancer cells and improves survival in mouse models of HCC.
“Senescence induction by inhibition of DNA replication kinase CDC7 has also been paired with a senolytic that disrupts mTOR signaling, inducing apoptosis in senescent human liver cancer cells and improving survival in mouse models of HCC (Wang et al. 2019).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Wang et al. 2019
The Abstract reports that CDC7 inhibition induced senescence selectively in TP53-mutant liver cancer cells and that mTOR inhibition caused apoptosis in CDC7-inhibitor-treated HCC cells. It also reports increased survival with the combination in one specific mouse model, MycOE;Trp53KO HCC; the claim’s plural “mouse models” overstates the survival finding. The paper reports tumour-growth inhibition in its other in vivo models. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMany of the genes in CisSig have been denoted as possible therapeutic targets in a variety of epithelial-based cancers.
“Furthermore, many of the genes have been denoted as possible therapeutic targets in a variety of epithelial-based cancers, such as CDC7 in oral squamous carcinoma30 and liver cancer31, ATP1B3 in gastric cancer32, and FKBP14 in ovarian cancer33.”
From Exploiting convergent phenotypes to derive a pan-cancer cisplatin response gene expression signature (2023) · cites this paper as [31]
In a mouse model of liver cancer, the mTOR inhibitor AZD8055 showed senolytic potential against cancer cells with senescence induced by small-molecule inhibitors of CDC7.
“In a mouse model of liver cancer, the mTOR inhibitor AZD8055 also showed senolytic potential against cancer cells with senescence induced by small- molecule inhibitors of CDC7 (ref. 207 ) .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [207]
Elevated expression of p16 in melanocytes and epidermal and dermal cells is associated with human aging.
“Elevated expression of p16 in melanocytes156 and epidermal and dermal cells157,158 is associated with human aging.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [156]
The paper’s Abstract discusses p16INK4A-positive cells in treated mouse liver tumors, not p16 expression in human skin during aging. Searches for melanocytes, epidermal and dermal cells, and skin aging found no passage addressing the attributed association. (LLM, conf=0.78)
Experimental — accuracy not yet measuredApproaches based on inducing senescence in a large fraction of tumors have the potential to enter clinical practice, especially when combined with adjuvant immunotherapy or senolytic therapy to remove harmful senescent escaper variants.
“Based on the preclinical experimental evidence enumerated here, approaches based on the induction of senescence in large fraction of tumors have the potential to enter the realm of the clinical practice, even more if combined with adjuvant immunotherapy or senolytic therapy to remove potentially harmful senescent escaper variants, as recently proposed.189,202,203”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [202]
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- Authors
- Wang, C., Vegna, S., Jin, H., Benedict, B., Lieftink, C., Ramirez, C., de Oliveira, R. L., Morris, B., Gadiot, J., Wang, W., du Chatinier, A., Wang, L., Gao, D., Evers, B., Jin, G., Xue, Z., Schepers, A., Jochems, F., Sanchez, A. M., Mainardi, S., te Riele, H., Beijersbergen, R. L., Qin, W., Akkari, L., & Bernards, R.
- Affiliations
- Shanghai Jiao Tong University (CN)
- The Netherlands Cancer Institute (NL)
- Fudan University (CN)
- Corresponding author
- Qin, Wenxin
- Akkari, Leila
- Bernards, René
- ORCID
- Venue
- Nature
- Published
- 2019-10-02
- Volume
- 574
- Issue
- 7777
- Pages
- 268-272
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6858884
- OpenAlex
- W2977409903
- Cited by
- 427
- References
- 31
- Citations by year
- 2026: 29 · 2025: 51 · 2024: 85 · 2023: 64 · 2022: 66 · 2021: 67 · 2020: 63 · 2018: 1 · 2012: 1
- FWCI
- 33.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- hepatocellular carcinoma, liver cancer, senescence, senolysis, TP53 mutation, sertraline, mTOR signaling, apoptosis, drug combination therapy, kinome screen, antidepressant repurposing
- MeSH terms
- Animals, Disease Models, Animal, Female, Liver Neoplasms, Male, Mice, Inbred BALB C, Mutation, Signal Transduction, Tumor Suppressor Protein p53, Cellular Senescence, Apoptosis, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Sertraline, Cell Line, Tumor, Mice, TOR Serine-Threonine Kinases, Molecular Targeted Therapy
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