The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.
CDK12 inhibition mediates DNA damage and is synergistic with sorafenib treatment in hepatocellular carcinoma
Abstract
OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the most frequent malignancies and a major leading cause of cancer-related deaths worldwide. Several therapeutic options like sorafenib and regorafenib provide only modest survival benefit to patients with HCC. This study aims to identify novel druggable candidate genes for patients with HCC. DESIGN: A non-biased CRISPR (clustered regularly interspaced short palindromic repeats) loss-of-function genetic screen targeting all known human kinases was performed to identify vulnerabilities of HCC cells. Whole-transcriptome sequencing (RNA-Seq) and bioinformatics analyses were performed to explore the mechanisms of the action of a cyclin-dependent kinase 12 (CDK12) inhibitor in HCC cells. Multiple in vitro and in vivo assays were used to study the synergistic effects of the combination of CDK12 inhibition and sorafenib. RESULTS: using short hairpin RNAs (shRNAs) or its inhibition by the covalent small molecule inhibitor THZ531 leads to robust proliferation inhibition. THZ531 preferentially suppresses the expression of DNA repair-related genes and induces strong DNA damage response in HCC cell lines. The combination of THZ531 and sorafenib shows striking synergy by inducing apoptosis or senescence in HCC cells. The synergy between THZ531 and sorafenib may derive from the notion that THZ531 impairs the adaptive responses of HCC cells induced by sorafenib treatment. CONCLUSION: Our data highlight the potential of CDK12 as a drug target for patients with HCC. The striking synergy of THZ531 and sorafenib suggests a potential combination therapy for this difficult to treat cancer.
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“Although CDK12 has only recently emerged as a potential vulnerability for different cancer types including Ewing sarcoma, triple-negative breast cancer, and hepatocellular carcinoma (Iniguez et al., 2018;Quereda et al., 2019;Wang et al., 2020)”
From Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer (2021) · cites this paper as Wang et al., 2020
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The Emerging Role of Transcription-Associated Cyclin-Dependent Kinases in Gastrointestinal Tumors
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Exploitation du défaut de réparation de l'ADN à l'aide de la stratégie d'inhibition de CDK
Orhan, E. (2022) · theses.fr (ABES) · doi:10.70675/40065dd4z1f5bz4361zaa67z59acc4e5d6c2
Goulding, J. R., Couwenbergh, S. T., Bekaert, S.-L., Sanders, E., Vloed, F. D., Amo-Addae, V., Eggermont, A., Wyn, J. D., Wever, K. D., Vleminckx, L., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117997
BindingDB (2023) · UC San Diego · doi:10.7270/q28k7f2w
Metadata
- Authors
- Wang, C., Wang, H., Lieftink, C., du Chatinier, A., Gao, D., Jin, G., Jin, H., Beijersbergen, R. L., Qin, W., & Bernards, R.
- Affiliations
- Shanghai Jiao Tong University (CN)
- The Netherlands Cancer Institute (NL)
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Fudan University (CN)
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
- Corresponding author
- Bernards, René
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2019-09-13
- Volume
- 69
- Issue
- 4
- Pages
- 727-736
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- OpenAlex
- W2972522329
- Cited by
- 107
- References
- 37
- Citations by year
- 2026: 10 · 2025: 4 · 2024: 19 · 2023: 19 · 2022: 26 · 2021: 16 · 2020: 11 · 2019: 2
- FWCI
- 10.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- the National Natural Science Foundation of China (81920108025, 81421001, 81672933, and 81874229)
- KWF Kankerbestrijding (Oncode Institute)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- hepatocellular carcinoma, CDK12, sorafenib, combination therapy, drug synergy, DNA damage response, DNA repair genes, CRISPR screen, apoptosis, cellular senescence, drug target identification
- MeSH terms
- Sorafenib, Anilides, Antineoplastic Agents, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Pyrimidines, Cyclin-Dependent Kinases, Cell Culture Techniques, Cell Line, Tumor
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