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.
Integrity signals
Registry
Cites
Statistics
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?
CDK12 has recently emerged as a potential vulnerability for different cancer types including Ewing sarcoma, triple-negative breast cancer, and hepatocellular carcinoma.
“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
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 · see citing works
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 · see citing works
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 · see citing works
Sorafenib in Advanced Hepatocellular Carcinoma
정, 재. (2008) · Cited by 5,606 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 1,059 · see citing works
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 600 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 410 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 274 · see citing works
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 245 · see citing works
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 206 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 39 · see citing works
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 · see citing works
Flagged first, then by citations
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 754 · see citing works
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 282 · see citing works
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 · see citing works
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 99 · see citing works
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 · see citing works
Niu, T., Li, K., Li, J., Zhou, Z., Hong, J.-E., Chen, X., Dong, X., He, Q., Cao, J., Yang, B., et al. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.114012 · Cited by 91 · see citing works
CDK12: A Potent Target and Biomarker for Human Cancer Therapy
Liang, S., Hu, L., Wu, Z., Chen, Z., Liu, S., Xu, X., & Qian, A. (2020) · Cells · doi:10.3390/cells9061483 · Cited by 75 · see citing works
Advanced Nanotheranostics of CRISPR/Cas for Viral Hepatitis and Hepatocellular Carcinoma
Kong, H., Ju, E., Yi, K., Xu, W., Lao, Y., Cheng, D., Zhang, Q., Tao, Y., Li, M., & Ding, J. (2021) · Advanced Science · doi:10.1002/advs.202102051 · Cited by 76 · see citing works
The Renaissance of Cyclin Dependent Kinase Inhibitors
Ettl, T., Schulz, D., & Bauer, R. J. (2022) · Cancers · doi:10.3390/cancers14020293 · Cited by 71 · see citing works
CDK12 and PAK2 as novel therapeutic targets for human gastric cancer
Liu, H., Shin, S. H., Chen, H., Liu, T., Li, Z., Hu, Y., Liu, F., Zhang, C., Kim, D. J., Liu, K., et al. (2020) · Theranostics · doi:10.7150/thno.46137 · Cited by 70 · see citing works
The Promise and Current Status of CDK12/13 Inhibition for the Treatment of Cancer
Tadesse, S., Duckett, D. R., & Monastyrskyi, A. (2020) · Future Medicinal Chemistry · doi:10.4155/fmc-2020-0240 · Cited by 57 · see citing works
CDK regulators—Cell cycle progression or apoptosis—Scenarios in normal cells and cancerous cells
Nilmani, D'costa, M., Bothe, A., Das, S., Kumar, S. U., Ramanathan, G., & Doss, C. G. P. (2023) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2022.11.008 · Cited by 59 · see citing works
Exploring liver cancer biology through functional genetic screens
Wang, C., Cao, Y., Yang, C. G., Bernards, R., & Qin, W. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00465-x · Cited by 58 · see citing works
Dual Inhibition of CDK12/CDK13 Targets Both Tumor and Immune Cells in Ovarian Cancer
Cheng, L., Zhou, S., Zhou, S., Shi, K., Cheng, Y., Cai, M., Ye, K., Lin, L., Zhang, Z., Jia, C., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-0222 · Cited by 54 · see citing works
Romualdo, G. R., Leroy, K., Costa, C. J. S., Bacil, G. P., Vanderborght, B., da Silva, T. C., Barbisan, L. F., Andraus, W., Devisscher, L., Câmara, N. O. S., et al. (2021) · Cancers · doi:10.3390/cancers13215583 · Cited by 52 · see citing works
Houles, T., Boucher, J., Lavoie, G., MacLeod, G., Lin, S., Angers, S., & Roux, P. P. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01754-x · Cited by 49 · see citing works
CRISPR screening identifies CDK12 as a conservative vulnerability of prostate cancer
Lei, H., Wang, Z., Jiang, D., Liu, F., Liu, M., Lei, X., Yang, Y., He, B., Yan, M., Huang, H. W., et al. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-04027-6 · Cited by 46 · see citing works
Sirtuin1-p53: A potential axis for cancer therapy
Yin, J., Lu, X.-T., Hou, M.-L., Cao, T., & Tian, Z. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115543 · Cited by 42 · see citing works
CDK12: cellular functions and therapeutic potential of versatile player in cancer
Pilařová, K., Herudek, J., & Blažek, D. (2020) · NAR Cancer · doi:10.1093/narcan/zcaa003 · Cited by 42 · see citing works
Hou, J., He, Z., Liu, T., Chen, D., Wang, B., Wen, Q., & Zheng, X. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.755053 · Cited by 44 · see citing works
CDK12 is hyperactivated and a synthetic-lethal target in BRAF-mutated melanoma
Houlès, T., Lavoie, G., Nourreddine, S., Cheung, W., Vaillancourt-Jean, É., Guérin, C. M., Bouttier, M., Grondin, B., Lin, S., Saba-El-Leil, M. K., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34179-8 · Cited by 39 · see citing works
Cellular senescence signaling in cancer: A novel therapeutic target to combat human malignancies
Fakhri, S., Moradi, S. Z., DeLiberto, L. K., & Bishayee, A. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.114989 · Cited by 38 · see citing works
Multiplexed kinase interactome profiling quantifies cellular network activity and plasticity
Golkowski, M. G., Lius, A., Sapre, T., Lau, H.-T., Moreno, T., Maly, D. J., & Ong, S. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.01.015 · Cited by 37 · see citing works
CDK12: a potential therapeutic target in cancer
Emadi, F., Teo, T., Rahaman, M. H., & Wang, S. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.09.035 · Cited by 35 · see citing works
Xu, B., Lei, H., Tong, T., Guan, Y., Wang, Y., Li, B., Zhang, S., Xing, C., Shuai, X., Huang, J., et al. (2024) · Nano Letters · doi:10.1021/acs.nanolett.4c01610 · Cited by 32 · see citing works
Diagnostic and prognostic values of AKR1C3 and AKR1D1 in hepatocellular carcinoma
Zhu, P., Feng, R., Lu, X., Liao, Y., Du, Z., Zhai, W., & Chen, K. (2021) · Aging · doi:10.18632/aging.202380 · Cited by 32 · see citing works
Sha, B., Sun, Y., Zhao, S., Li, M., Huang, W., Li, Z., Shi, J., Han, X., Li, P., Hu, T., et al. (2022) · Cell Biology and Toxicology · doi:10.1007/s10565-021-09686-x · Cited by 31 · see citing works
Cellular Senescence in Hepatocellular Carcinoma: The Passenger or the Driver?
Cai, X., Guillot, A., & Liu, H. (2022) · Cells · doi:10.3390/cells12010132 · Cited by 30 · see citing works
CDK12 regulates co-transcriptional splicing and RNA turnover in human cells
Magnuson, B., Bedi, K., Narayanan, I. V., Bartkowiak, B., Blinkiewicz, H., Paulsen, M. T., Greenleaf, A. L., & Ljungman, M. E. (2022) · iScience · doi:10.1016/j.isci.2022.105030 · Cited by 29 · see citing works
Dai, W., Wu, J., Peng, X., Hou, W., Huang, H., Cheng, Q., Liu, Z., Luyten, W., Schoofs, L., Zhou, J., et al. (2022) · Clinical and Translational Medicine · doi:10.1002/ctm2.1087 · Cited by 28 · see citing works
Artificial intelligence — upping the game in gastrointestinal endoscopy?
Rees, C. J., & Koo, S. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0178-y · Cited by 26 · see citing works
Current progress and novel strategies that target CDK12 for drug discovery
Lei, P., Zhang, J., Liao, P., Ren, C., Wang, J., & Wang, D. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114603 · Cited by 26 · see citing works
Li, T.-T., Mou, J., Pan, Y., Huo, F., Du, W., Liang, J., Wang, Y., Zhang, L., & Pei, D. (2021) · Journal of Biomedical Science · doi:10.1186/s12929-021-00752-4 · Cited by 25 · see citing works
Sun, R., Wei, T., Ding, D., Zhang, J., Chen, S., He, H. H., Wang, L., & Huang, H. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2205509119 · Cited by 25 · see citing works
Wu, Z., Zhang, W., Chen, L., Wang, T., Wang, X., Shi, H., Zhang, L., Zhong, M., Shi, X., Mao, X., et al. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107097 · Cited by 25 · see citing works
Chang, Y., Wang, X., Yang, J., Tien, J. C.-Y., Mannan, R., Cruz, G., Zhang, Y., Vo, J. N., Magnuson, B., Mahapatra, S., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101752 · Cited by 24 · see citing works
Insights into Sorafenib resistance in hepatocellular carcinoma: Mechanisms and therapeutic aspects
Yousef, E. H., Gayar, A. M. E., & El‐Magd, N. F. A. (2025) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2025.104765 · Cited by 24 · see citing works
Nie, Y., Yan, J., Huang, X., Jiang, T., Zhang, S., & Zhang, G. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155767 · Cited by 23 · see citing works
Liu, M., Ruan, X., Liu, X., Dong, W., Wang, D., Yang, C., Liu, L., Wang, P., Zhang, M., & Xue, Y. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05426-z · Cited by 22 · see citing works
Surfaceome CRISPR screen identifies OLFML3 as a rhinovirus-inducible IFN antagonist
Mei, H., Zha, Z., Wang, W., Xie, Y., Huang, Y., Li, W., Wei, D., Zhang, X., Xie, J., Liu, J., et al. (2021) · Genome biology · doi:10.1186/s13059-021-02513-w · Cited by 20 · see citing works
Yu, T., Wang, F., Li, S., Guo, W., Li, Q., Qian, Y., Li, L., Zhao, H., Zhang, Y., Gao, W., et al. (2023) · Hepatology · doi:10.1097/hep.0000000000000559 · Cited by 21 · see citing works
Yousef, E. H., El‐Magd, N. F. A., & Gayar, A. M. E. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.121735 · Cited by 20 · see citing works
Shyamsunder, P., Sridharan, S. P., Madan, V., Dakle, P., Cao, Z., Kanojia, D., Chng, W. J., Ong, S. T., & Koeffler, H. P. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031207 · Cited by 19 · see citing works
Liu, Y., Li, Z., Zhang, J., Liu, W., Guan, S., Zhan, Y., Fang, Y., Li, Y., Deng, H., & Shen, Z. (2024) · British Journal of Cancer · doi:10.1038/s41416-024-02719-2 · Cited by 19 · see citing works
The dual role of p63 in cancer
Xu, Y., Yang, X., Xiong, Q., Han, J., & Zhu, Q. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1116061 · Cited by 18 · see citing works
Ang, H. X., Sutiman, N., Deng, X., Liu, A., Cerda-Smith, C. G., Hutchinson, H. M., Kim, H., Bartelt, L. C., Chen, Q., Barrera, A., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2221448120 · Cited by 18 · see citing works
CDK12 is a potential biomarker for diagnosis, prognosis and immunomodulation in pan-cancer
Lu, K.-Q., Li, Z., Zhang, Q., Yin, Q., Zhang, Y., Ni, W., Jiang, L.-Z., He, W., & Wang, B. (2024) · Scientific Reports · doi:10.1038/s41598-024-56831-7 · Cited by 19 · see citing works
Frei, K., Schecher, S., Daher, T., Hörner, N., Richter, J., Hildebrand, U., Schindeldecker, M., Witzel, H. R., Tsaur, I., Porubský, Š., et al. (2023) · International Journal of Cancer · doi:10.1002/ijc.34778 · Cited by 17 · see citing works
Not the comfy chair! Cancer drugs that act against multiple active sites
Booth, L. A., Poklepovic, A. S., & Dent, P. (2019) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2019.1691526 · Cited by 16 · see citing works
Cyclin-dependent kinase 12 (CDK12) in chordoma: prognostic and therapeutic value
Thanindratarn, P., Dean, D. C., Feng, W., Wei, R., Nelson, S. D., Hornicek, F. J., & Duan, Z. (2020) · European Spine Journal · doi:10.1007/s00586-020-06543-z · Cited by 15 · see citing works
Transcription-associated cyclin-dependent kinase 12 (CDK12) as a potential target for cancer therapy
Wu, W., Yu, S., & Yu, X. (2022) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2022.188842 · Cited by 16 · see citing works
van der Noord, V. E., van der Stel, W., Louwerens, G., Verhoeven, D., Kuiken, H. J., Lieftink, C., Grandits, M., Ecker, G. F., Beijersbergen, R. L., Bouwman, P., et al. (2023) · Breast Cancer Research · doi:10.1186/s13058-023-01648-x · Cited by 15 · see citing works
Hu, S., Liu, B., Shang, J., Guo, Q., Lu, T., Zhou, X., Zhou, X., & Wang, X. (2024) · British Journal of Cancer · doi:10.1038/s41416-024-02919-w · Cited by 14 · see citing works
Yang, Q., & Wu, G. (2021) · Gastroenterología y Hepatología · doi:10.1016/j.gastrohep.2021.11.007 · Cited by 14 · see citing works
A Combined Antitumor Strategy Mediated by a New Targeted Nanosystem to Hepatocellular Carcinoma
Farinha, D., Migawa, M. T., Sarmento‐Ribeiro, A. B., & Faneca, H. (2021) · International Journal of Nanomedicine · doi:10.2147/ijn.s302288 · Cited by 14 · see citing works
Recent Developments and Evolving Therapeutic Strategies in KMT2A ‐Rearranged Acute Leukemia
Yin, L., Wan, L., Zhang, Y., Hua, S., & Shao, X. (2024) · Cancer Medicine · doi:10.1002/cam4.70326 · Cited by 13 · see citing works
Anti-hepatocellular carcinoma activity of the cyclin-dependent kinase inhibitor AT7519
Karaś, K., Karwaciak, I., Chałaśkiewicz, K., Sałkowska, A., Pastwińska, J., Bachorz, R. A., & Ratajewski, M. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115002 · Cited by 12 · see citing works
Wu, D., Yin, H., Yang, C., Zhang, Z.-M., Fang, F., Wang, J., Li, X., Xie, Y., Hu, X., Zhuo, R., et al. (2024) · BMC Cancer · doi:10.1186/s12885-024-12691-y · Cited by 12 · see citing works
Bai, Y., Liu, Z., Li, Y., Zhao, H., Lai, C., Zhao, S., Chen, K., Luo, C., Yang, X., & Wang, F. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c01697 · Cited by 12 · see citing works
Gao, L., Wang, J., Chen, J., Zhang, X., Zhang, M., Wang, S.-L., & Zhao, C. (2023) · Applied Biochemistry and Biotechnology · doi:10.1007/s12010-023-04436-7 · Cited by 11 · see citing works
RAD51 Inhibition Shows Antitumor Activity in Hepatocellular Carcinoma
Pan, M., Sha, Y., Qiu, J., Chen, Y., Liu, L., Luo, M., Huang, A., & Xia, J. L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24097905 · Cited by 12 · see citing works
Liu, S., Wu, J., Lu, X., Guo, C., Zheng, Q., Wang, Y., Hu, Q., Bian, S., Luo, L., Cheng, Q., et al. (2023) · Experimental Cell Research · doi:10.1016/j.yexcr.2023.113613 · Cited by 10 · see citing works
Dai, W., Xie, D., Huang, H., Li, J., Guo, C., Cao, F., Yang, L., Zhong, C., & Liu, S. (2024) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2024.101173 · Cited by 10 · see citing works
CRISPR/Cas9 genetic screens in hepatocellular carcinoma gene discovery
Chiu, C. H. (2023) · Current Research in Biotechnology · doi:10.1016/j.crbiot.2023.100127 · Cited by 10 · see citing works
Targeting Transcriptional Cyclin-Dependent Kinases in Cancer
Kołodziejczyk, A., & Siciński, P. (2025) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-23-0677 · Cited by 9 · see citing works
Ma, B., Shi, S., Guo, W., Zhang, H., Zhao, Z., & An, H. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.3c06142 · Cited by 8 · see citing works
Contreras, L., Rodríguez‐Gil, A., Muntané, J., & de la Cruz, J. (2022) · Cancers · doi:10.3390/cancers14051204 · Cited by 8 · see citing works
Antitumoral activity of a CDK12 inhibitor in colorectal cancer through a liposomal formulation
Díaz‐Tejeiro, C., Arenas-Moreira, M., Sanvicente, A., Paniagua‐Herranz, L., Clemente-Casares, P., Bravo, I., Alonso‐Moreno, C., Nieto‐Jiménez, C., & Ocaña, A. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117165 · Cited by 7 · see citing works
Roles of CDK12 mutations in PCa development and treatment
Jiang, C., Hong, Z., Liu, S., Hong, Z., & Dai, B. (2024) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2024.189247 · Cited by 7 · see citing works
Are we ready for targeted therapy combinations in HCC?
Cinnamon, E., & Pikarsky, E. (2020) · Gut · doi:10.1136/gutjnl-2019-319780 · Cited by 7 · see citing works
Zhang, X., Jiang, M., Zhang, X., Zhang, J., Guo, H., & Wu, C. (2022) · Clinics and Research in Hepatology and Gastroenterology · doi:10.1016/j.clinre.2022.101877 · Cited by 6 · see citing works
Mei, H., Gu, Q., Wang, W., Meng, Y., Jiang, L., & Liu, J. (2022) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2022.07.026 · Cited by 6 · see citing works
CDK12 /13 dual inhibitors are potential therapeutics for acute myeloid leukemia
Savoy, L., Long, N., Lee, H., Chen, R., Allen, B., Lin, H., Tognon, C. E., Malhotra, S. V., Tyner, J. W., & Zhang, H. (2023) · British Journal of Haematology · doi:10.1111/bjh.18843 · Cited by 6 · see citing works
Li, Z., Li, X., Seebacher, N. A., Liu, X., Wu, W., Yu, S., Hornicek, F. J., Huang, C., & Duan, Z. (2024) · Carcinogenesis · doi:10.1093/carcin/bgae051 · Cited by 5 · see citing works
Zhang, H., Xing, C., Yan, B., Lei, H., Guan, Y., Zhang, S., Kang, Y., & Pang, J. (2024) · Biomacromolecules · doi:10.1021/acs.biomac.4c00260 · Cited by 5 · see citing works
Wu, C., Ho, H. J., Wu, C., Chen, Y., Lee, T., Hsu, Y., & Lin, J. (2020) · Gut · doi:10.1136/gutjnl-2020-321932 · Cited by 5 · see citing works
Liu, Q., Dai, G.-R., Wang, X., Wang, L., Li, L., Wu, Z., & Xia, R.-X. (2022) · Cancer Gene Therapy · doi:10.1038/s41417-021-00415-4 · Cited by 5 · see citing works
Wang, B., Wang, Y., Wen, Y., Zhang, Y., Ni, W., Tang, T., Cao, J.-Y., Yin, Q., Jiang, W., Yin, D., et al. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.05.012 · Cited by 5 · see citing works
Donovan, M. G., Galbraith, M. D., & Espinosa, J. M. (2022) · Scientific Reports · doi:10.1038/s41598-022-26860-1 · Cited by 5 · see citing works
Ju, N., Zhao, L., Yin, S., Yang, X., Zhou, J., Gao, J., & Qi, F. (2026) · International Journal of Cancer · doi:10.1002/ijc.70442 · Cited by 4 · see citing works
Lier, S., Markusson, S., Kocijancic, A., Narum, M., Lund, S. O., Böllering, B., Lipsa, A., Soegaard, M. D., Rein, I. D., Sántha, P., et al. (2026) · EMBO Molecular Medicine · doi:10.1038/s44321-026-00393-w · Cited by 4 · see citing works
Zhang, Y., Tang, T., Ni, W., Li, Z.-T., Jiang, L.-Y.-Z., Wang, Y., Zhou, X., Cao, J.-Y., Yin, Q., Jiang, W., et al. (2024) · International Journal of Biological Sciences · doi:10.7150/ijbs.90872 · Cited by 4 · see citing works
Gong, L., Wang, W., Yu, F., Deng, Z., Luo, N., Zhang, X., Chen, J., & Peng, J. (2024) · Scientific Reports · doi:10.1038/s41598-024-65496-1 · Cited by 4 · see citing works
Targeting DNA repair to enhance the efficacy of sorafenib in hepatocellular carcinoma
Samadaei, M., Senfter, D., Madlener, S., Uranowska, K., Häfner, C., Trauner, M. A., Rohr‐Udilova, N., & Pinter, M. (2022) · Journal of Cellular Biochemistry · doi:10.1002/jcb.30340 · Cited by 4 · see citing works
The role of CDK12 in tumor biology
Dzimková, M., Procházková, J., Klát, J., & Kohoutek, J. (2020) · Klinicka onkologie · doi:10.14735/amko2020260 · Cited by 3 · see citing works
Quest for discovering novel CDK12 inhibitor
Debnath, A., Singh, R. K., Mazumder, R., Mazumder, A., Srivastava, S., Chaudhary, H., Mangal, S., Sanchitra, J., Tyagi, P. K., Singh, S. K., et al. (2024) · Journal of Receptors and Signal Transduction · doi:10.1080/10799893.2024.2441185 · Cited by 3 · see citing works
Huang, D., Xiong, Z., Zhong, B., Li, X., Mohamed, S. A., Sun, J., Xu, H., Guo, J., Deng, Z., Li, X., et al. (2025) · Journal of Gastrointestinal Oncology · doi:10.21037/jgo-2025-392 · Cited by 3 · see citing works
Lin, Y., Liu, H., Liao, W.-C., Wang, Y., Zhang, B.-C., Wan, S.-W., Chen, C., & Chang, C. (2025) · Oncology Reports · doi:10.3892/or.2025.8987 · Cited by 2 · see citing works
CDK12 and CDK13 in oncology: from RNA regulation to therapeutic targeting
Dudkiewicz-Garbicz, J., & Wlodarski, P. K. (2026) · Cellular Oncology · doi:10.1007/s13402-025-01131-z · Cited by 2 · see citing works
Roles of CDK12/CDK13 and development of inhibitors and degraders
Li, Z. F., Ke, Y., Zhang, R., Zhang, R., & Zhang, L. (2026) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2026.119077 · Cited by 3 · see citing works
Targeting Cellular Senescence: A New Therapeutic Axis in Chronic Liver Disease
Li, J., Xiang, Z., Xu, Y., Luo, X., Jiang, Y. X., Huang, Y., Yang, Z., Chen, R., & (112147), X. X. (2026) · Engineering · doi:10.1016/j.eng.2026.02.019 · Cited by 2 · see citing works
Low Pi stress enhances the sensitivity of hepatocellular carcinoma to sorafenib
Bi, Q., Deng, Z.-Q., Lv, Y., Liu, Y., Xie, C.-S., He, Y., & Tang, Q. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115593 · Cited by 2 · see citing works
Development of CDK12 as a Cancer Therapeutic Target and Related Inhibitors
Chen, B., & Liu, J. (2024) · Current Cancer Drug Targets · doi:10.2174/0115680096307629240611104728 · Cited by 2 · see citing works
Ang, H. X., Sutiman, N., Deng, X. L., Bartelt, L. C., Chen, Q., Barrera, A., Lin, J., Sheng, J., McDowell, I. C., Reddy, T. E., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.03.433762 · Cited by 2 · see citing works
Hu, R., Liang, X., Li, Q., & Liu, Y. Z. (2022) · Journal of Oncology · doi:10.1155/2022/4869732 · Cited by 1 · see citing works
Jing, Y., Xing, Y., Liu, Y., Zhang, N., Pan, Y., Zhang, W., Zhu, C., Zhenyue, Z., Zhang, G., Li, J.-C., et al. (2026) · Functional & Integrative Genomics · doi:10.1007/s10142-026-01914-z · Cited by 1 · see citing works
Hu, L., Zhong, W., Wang, L., Liang, S., 贾云献, Wu, Z., Shen, J., Sun, J., & Qian, A. (2026) · Bone and Joint Research · doi:10.1302/2046-3758.157.bjr-2025-0343.r1 · Cited by 1 · see citing works
Yang, Q., & Wu, G. (2022) · Gastroenterología y Hepatología (English Edition) · doi:10.1016/j.gastre.2021.11.004 · Cited by 1 · see citing works
Data from Dual Inhibition of CDK12/CDK13 Targets Both Tumor and Immune Cells in Ovarian Cancer
Cheng, L., Zhou, S., Zhou, S., Shi, K., Cheng, Y., Cai, M., Ye, K., Lin, L., Zhang, Z., Jia, C., et al. (2023) · doi:10.1158/0008-5472.c.6514152.v1
Mei, H., Zha, Z., Wang, W. J., Xie, Y., Huang, Y., Li, W., Wei, D., Zhang, X., Qu, J., & Liu, J. (2021) · Figshare · doi:10.6084/m9.figshare.16862824
- 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
