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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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
Citations
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
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
Cheng, A.-L., Kang, Y.-K., Chen, Z., Tsao, C.-J., Qin, S., Kim, J. S., Luo, R., Feng, J., Ye, S., Yang, T.-S., et al. (2009) · The Lancet Oncology · doi:10.1016/s1470-2045(08)70285-7 · Cited by 5,832
Sorafenib in Advanced Hepatocellular Carcinoma
정, 재. (2008) · Cited by 5,586
The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206
Li, W., Xu, H., Xiao, T., Cong, L., Love, M. I., Zhang, F., Irizarry, R. A., Liu, J. S., Brown, M., & Liu, X. S. (2014) · Genome Biology · doi:10.1186/s13059-014-0554-4 · Cited by 2,684
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
Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR
Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., Beijersbergen, R. L., Bardelli, A., & Bernards, R. (2012) · Nature · doi:10.1038/nature10868 · Cited by 2,051
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
A large-scale RNAi screen in human cells identifies new components of the p53 pathway
Berns, K., Hijmans, E. M., Mullenders, J., Brummelkamp, T. R., Velds, A., Heimerikx, M., Kerkhoven, R. M., Madiredjo, M., Nijkamp, W., Weigelt, B., et al. (2004) · Nature Cell Biology · doi:10.1038/nature02371 · Cited by 1,080
Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer
Wu, Y.-M., Cieslik, M. P., Lonigro, R. J., Vats, P., Reimers, M. A., Cao, X., Yu, N., Wang, L., Kunju, L. P., Sarkar, N. D., et al. (2018) · Cell · doi:10.1016/j.cell.2018.04.034 · Cited by 620
Sharova, L. V., Sharov, A. A., Nedorezov, T., Piao, Y., Shaik, N., & Ko, M. S. H. (2009) · DNA Research · doi:10.1093/dnares/dsn030 · Cited by 591
Blazek, D., Kohoutek, J., Bartholomeeusen, K., Johansen, E., Hulinkova, P., Luo, Z., Cimermancic, P., Ule, J., & Peterlin, B. M. (2011) · Genes & Development · doi:10.1101/gad.16962311 · Cited by 522
CRISPR knockout screening outperforms shRNA and CRISPRi in identifying essential genes
Evers, B., Jastrzebski, K., Heijmans, J. P. M., Grernrum, W., Beijersbergen, R. L., & Bernards, R. (2016) · Nature Biotechnology · doi:10.1038/nbt.3536 · Cited by 431
MED12 Controls the Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling
Huang, S., Hölzel, M., Knijnenburg, T., Schlicker, A., Roepman, P., McDermott, U., Garnett, M., Grernrum, W., Sun, C., Prahallad, A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.10.035 · Cited by 430
Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors
Zhang, T., Kwiatkowski, N., Olson, C. M., Dixon-Clarke, S. E., Abraham, B. J., Greifenberg, A. K., Ficarro, S. B., Elkins, J. M., Liang, Y., Hannett, N. M., et al. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2166 · Cited by 374
Bajrami, I., Frankum, J. R., Konde, A., Miller, R. E., Rehman, F. L., Brough, R., Campbell, J., Sims, D., Rafiq, R., Hooper, S., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-2541 · Cited by 373
CDK12 regulates DNA repair genes by suppressing intronic polyadenylation
Dubbury, S. J., Boutz, P. L., & Sharp, P. A. (2018) · Nature · doi:10.1038/s41586-018-0758-y · Cited by 318
Chen, K., Chen, H., Tai, W., Feng, W.-C., Hsu, C., Chen, P., & Cheng, A. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.110.175786 · Cited by 317
Johnson, S. F., Cruz, C., Greifenberg, A. K., Dust, S., Stover, D. G., Chi, D., Primack, B., Cao, S., Bernhardy, A. J., Coulson, R., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.10.077 · Cited by 291
In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer
Rudalska, R., Dauch, D., Longerich, T., McJunkin, K., Wuestefeld, T., Kang, T.-W., Hohmeyer, A., Pesic, M., Leibold, J., von Thun, A., et al. (2014) · Nature Medicine · doi:10.1038/nm.3679 · Cited by 282
Dauch, D., Rudalska, R., Cossa, G., Nault, J., Kang, T.-W., Wüestefeld, T., Hohmeyer, A., Imbeaud, S., Yevsa, T., Hoenicke, L., et al. (2016) · Nature Medicine · doi:10.1038/nm.4107 · Cited by 280
Functional genomics identifies therapeutic targets for MYC-driven cancer
Toyoshima, M., Howie, H. L., Imakura, M., Walsh, R. M., Annis, J. E., Chang, A. N., Frazier, J. P., Chau, B. N., Loboda, A. P., Linsley, P. S., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1121119109 · Cited by 252
Tovar, V., Cornellà, H., Moeini, A., Vidal, S. J., Hoshida, Y., Sia, D., Peix, J., Cabellos, L., Alsinet, C., Torrecilla, S., et al. (2015) · Gut · doi:10.1136/gutjnl-2015-309501 · Cited by 204
Liang, K., Gao, X., Gilmore, J. M., Florens, L. A., Washburn, M. P., Smith, E. R., & Shilatifard, A. (2015) · Molecular and Cellular Biology · doi:10.1128/mcb.01426-14 · Cited by 194
The structure and substrate specificity of human Cdk12/Cyclin K
Bösken, C. A., Farnung, L., Hintermair, C., Merzel Schachter, M., Vogel-Bachmayr, K., Blazek, D., Anand, K., Fisher, R. P., Eick, D., & Geyer, M. (2014) · Nature Communications · doi:10.1038/ncomms4505 · Cited by 191
Eggelpoël, M.-J. B.-V., Chettouh, H., Fartoux, L., Aoudjehane, L., Barbu, V. D., Rey, C., Priam, S., Housset, C., Rosmorduc, O., & Desbois‐Mouthon, C. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.02.019 · Cited by 182
EWS/FLI confers tumor cell synthetic lethality to CDK12 inhibition in Ewing sarcoma
Iniguez, A. B., Stolte, B., Wang, E. J., Conway, A. S., Alexe, G., Dharia, N. V., Kwiatkowski, N., Zhang, T., Abraham, B. J., Mora, J., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2017.12.009 · Cited by 173
Ekumi, K. M., Paculová, H., Lenasi, T., Pospíchalová, V., Bösken, C. A., Rybaříková, J., Bryja, V., Geyer, M., Blažek, D., & Barborič, M. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv101 · Cited by 145
Chen, H.-H., Wang, Y.-C., & Fann, M. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.7.2736-2745.2006 · Cited by 144
CDK12: an emerging therapeutic target for cancer
Lui, G. Y. L., Grandori, C., & Kemp, C. J. (2018) · Journal of Clinical Pathology · doi:10.1136/jclinpath-2018-205356 · Cited by 132
Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression
Rusan, M., Li, K., Li, Y. Y., Christensen, C. L., Abraham, B. J., Kwiatkowski, N. P., Buczkowski, K. A., Bockorny, B., Chen, T., Li, S., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0461 · Cited by 128
Wang, C., Jin, H., Gao, D., Lieftink, C., Evers, B., Jin, G., Zheng, X., Wang, L., Beijersbergen, R. L., Qin, W., et al. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.07.004 · Cited by 93
CDK13/CDC2L5 interacts with L-type cyclins and regulates alternative splicing
Chen, H.-H., Wong, Y., Genevière, A., & Fann, M. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.01.049 · Cited by 83
A CRISPR screen identifies CDK7 as a therapeutic target in hepatocellular carcinoma
Wang, C., Jin, H., Gao, D., Wang, L., Evers, B., Zheng, X., Jin, G., Lieftink, C., Beijersbergen, R. L., Qin, W., et al. (2018) · Cell Research · doi:10.1038/s41422-018-0020-z · Cited by 61
Wang, C., Gao, D., Guo, K., Kang, X., Jiang, K., Sun, C., Li, Y., Sun, L., Shu, H., Jin, G., et al. (2012) · BMC Cancer · doi:10.1186/1471-2407-12-166 · Cited by 40
BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors
Paculová, H., Kramara, J., Šimečková, Š., Fedr, R., Souček, K., Hylse, O., Paruch, K., Svoboda, M., Mistrík, M., & Kohoutek, J. (2017) · Tumor Biology · doi:10.1177/1010428317727479 · Cited by 34
Cited by
Sorted by citations
Targeted therapy for hepatocellular carcinoma
Huang, A., Yang, X., Chung, W. Y., Dennison, A. R., & Zhou, J. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00264-x · Cited by 767
CDK inhibitors in cancer therapy, an overview of recent development.
Zhang, M., Zhang, L., Hei, R., Li, X., Cai, H., Wu, X., Zheng, Q., & Cai, C. (2021) · PubMed Central · Cited by 280
Chen, Y., Li, L., Lan, J., Cui, Y., Rao, X., Zhao, J., Xing, T., Ju, G., Song, G., Lou, J., et al. (2022) · Molecular Cancer · doi:10.1186/s12943-021-01466-9 · Cited by 126
Targeting CDK12 for Cancer Therapy: Function, Mechanism, and Drug Discovery
Liu, H., Liu, K., & Dong, Z. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-2245 · Cited by 101
Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer
Dieter, S. M., Siegl, C., Codó, P. L., Huerta, M., Ostermann-Parucha, A. L., Schulz, E., Zowada, M. K., Martin, S., Laaber, K., Nowrouzi, A., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109394 · Cited by 95
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
