The DOI matches its Crossref record; 30 of the 31 references it cites were found in a registry or an index.
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 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
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“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]
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“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]
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“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]
Experimental — accuracy not yet measuredIn the citing paper
“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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Cites
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21492 · Cited by 84,109
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
Sorafenib in advanced hepatocellular carcinoma
Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J.-F., de Oliveira, A. C., Santoro, A., Raoul, J.-L., Forner, A., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0708857 · Cited by 13,097
Llovet, J. M., Kelley, R. K., Villanueva, A., Singal, A. G., Pikarsky, E., Roayaie, S., Lencioni, R., Koike, K., Zucman-Rossi, J., & Finn, R. S. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-020-00240-3 · Cited by 7,055
Sorafenib in Advanced Hepatocellular Carcinoma
정, 재. (2008) · Cited by 5,586
Llovet, J. M., Zucman-Rossi, J., Pikarsky, E., Sangro, B., Schwartz, M., Sherman, M., & Gores, G. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.18 · Cited by 2,531
Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma
Ally, A., Balasundaram, M., Carlsen, R., Chuah, E., Clarke, A., Dhalla, N., Holt, R. A., Jones, S. J. M., Lee, D., Ma, Y., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.046 · Cited by 2,490
Self-citationThe comet assay: a method to measure DNA damage in individual cells
Olive, P. L., & Banáth, J. P. (2006) · Nature Protocols · doi:10.1038/nprot.2006.5 · Cited by 1,845
Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice
Chang, J., Wang, Y., Shao, L., Laberge, R.-M., Demaria, M., Campisi, J., Janakiraman, K., Sharpless, N. E., Ding, S., Feng, W., et al. (2016) · Nature Medicine · doi:10.1038/nm.4010 · Cited by 1,819
Genetic landscape and biomarkers of hepatocellular carcinoma
Zucman-Rossi, J., Villanueva, A., Nault, J.-C., & Llovet, J. M. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.05.061 · Cited by 1,325
Cited by
Sorted by citations
Vogel, A., Meyer, T., Sapisochin, G., Salem, R., & Saborowski, A. (2022) · The Lancet · doi:10.1016/s0140-6736(22)01200-4 · Cited by 2,427
Matthews, H. K., Bertoli, C., & de Bruin, R. A. M. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00404-3 · Cited by 1,506
Senescence and the SASP: many therapeutic avenues
Birch, J., & Gil, J. (2020) · Genes & Development · doi:10.1101/gad.343129.120 · Cited by 1,177
“For example, the SASP produced by preneoplastic hepatocytes recruits immature myeloid cells that inhibit NK cells, therefore contributing to HCC progression (Eggert et al. 2016).”
BackgroundSenolytic CAR T cells reverse senescence-associated pathologies
Amor, C., Feucht, J., Leibold, J., Ho, Y.-J., Zhu, C., Alonso-Curbelo, D., Mansilla-Soto, J., Boyer, J. A., Li, X., Giavridis, T., et al. (2020) · Nature · doi:10.1038/s41586-020-2403-9 · Cited by 1,098
Exploiting senescence for the treatment of cancer
Wang, L., Lankhorst, L., & Bernards, R. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-022-00450-9 · Cited by 867
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Metadata
- 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
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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