Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer
Open accessAbstract
Epigenetic regulation enables tumors to respond to changing environments during tumor progression and metastases and facilitates treatment resistance. Targeting chromatin modifiers or catalytic effectors of transcription is an emerging anti-cancer strategy. The cyclin-dependent kinases (CDKs) 12 and 13 phosphorylate the C-terminal domain of RNA polymerase II, regulating transcription and co-transcriptional processes. Here we report the development of SR-4835, a highly selective dual inhibitor of CDK12 and CDK13, which disables triple-negative breast cancer (TNBC) cells. Mechanistically, inhibition or loss of CDK12/CDK13 triggers intronic polyadenylation site cleavage that suppresses the expression of core DNA damage response proteins. This provokes a "BRCAness" phenotype that results in deficiencies in DNA damage repair, promoting synergy with DNA-damaging chemotherapy and PARP inhibitors.
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Synergy between CDK12 kinase inhibitors and drugs causing DNA damage or interfering with DNA damage repair pathways has recently been reported in other tumor entities.
“Synergy between CDK12 kinase inhibitors and drugs causing DNA damage or interfering with DNA damage repair pathways has recently been reported in other tumor entities (Quereda et al., 2019).”
From Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer (2021) · cites this paper as Quereda et al., 2019
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 Quereda et al., 2019
Cites
Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012
Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D. M., Forman, D., & Bray, F. (2015) · International Journal of Cancer · doi:10.1002/ijc.29210 · Cited by 28,766 · see citing works
Siegel, R. L., Miller, K. D., & Jemal, A. (2017) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21387 · Cited by 14,712 · see citing works
Chou, T.-C., & Talalay, P. (1984) · Advances in Enzyme Regulation · doi:10.1016/0065-2571(84)90007-4 · Cited by 7,178 · see citing works
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
Farmer, H., McCabe, N., Lord, C. J., Tutt, A. N. J., Johnson, D. A., Richardson, T. B., Santarosa, M., Dillon, K. J., Hickson, I., Knights, C., et al. (2005) · Nature · doi:10.1038/nature03445 · Cited by 6,683 · see citing works
Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities
Nusse, R., & Clevers, H. (2017) · Cell · doi:10.1016/j.cell.2017.05.016 · Cited by 4,342 · see citing works
Cell cycle, CDKs and cancer: a changing paradigm
Malumbres, M., & Barbacid, M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2602 · Cited by 3,957 · see citing works
Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from <i>BRCA</i> Mutation Carriers
Fong, P. C., Boss, D. S., Yap, T. A., Tutt, A., Wu, P., Mergui-Roelvink, M., Mortimer, P., Swaisland, H., Lau, A., O'Connor, M. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0900212 · Cited by 3,634 · see citing works
Olaparib for Metastatic Breast Cancer in Patients with a Germline <i>BRCA</i> Mutation
Robson, M., Im, S.-A., Senkus, E., Xu, B., Domchek, S. M., Masuda, N., Delaloge, S., Li, W., Tung, N., Armstrong, A., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1706450 · Cited by 3,294 · see citing works
Talazoparib in Patients with Advanced Breast Cancer and a Germline <i>BRCA</i> Mutation
Litton, J. K., Rugo, H. S., Ettl, J., Hurvitz, S. A., Gonçalves, A., Lee, K.-H., Fehrenbacher, L., Yerushalmi, R., Mina, L. A., Martin, M., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1802905 · Cited by 2,175 · see citing works
ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response
Blackford, A. N., & Jackson, S. P. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.05.015 · Cited by 1,953 · see citing works
The 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 · see citing works
Malumbres, M. (2014) · Genome biology · doi:10.1186/gb4184 · Cited by 1,683 · see citing works
Lord, C. J., & Ashworth, A. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2015.21 · Cited by 1,257 · see citing works
DNA damage and the balance between survival and death in cancer biology
Roos, W. P., Thomas, A. D., & Kaina, B. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2015.2 · Cited by 1,189 · see citing works
Targeting transcription regulation in cancer with a covalent CDK7 inhibitor
Kwiatkowski, N. P., Zhang, T., Rahl, P. B., Abraham, B. J., Reddy, J., Ficarro, S. B., Dastur, A., Amzallag, A., Ramaswamy, S., Tesar, B. M., et al. (2014) · Nature · doi:10.1038/nature13393 · Cited by 865 · see citing works
Triple-negative breast cancer: disease entity or title of convenience?
Carey, L., Winer, E. P., Viale, G., Cameron, D., & Gianni, L. (2010) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2010.154 · Cited by 780 · see citing works
Clinical Diagnosis and Management of Breast Cancer
McDonald, E. S., Clark, A. S., Tchou, J. C., Zhang, P. J., & Freedman, G. M. (2016) · Journal of Nuclear Medicine · doi:10.2967/jnumed.115.157834 · Cited by 619 · see citing works
The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance
Bouwman, P., & Jonkers, J. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3342 · Cited by 615 · 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
DNA-Damaging Agents in Cancer Chemotherapy: Serendipity and Chemical Biology
Cheung-Ong, K., Giaever, G. N., & Nislow, C. (2013) · Chemistry & Biology · doi:10.1016/j.chembiol.2013.04.007 · Cited by 585 · 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
The code and beyond: transcription regulation by the RNA polymerase II carboxy-terminal domain
Harlen, K. M., & Churchman, L. S. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.10 · Cited by 499 · see citing works
Zhang, X., Claerhout, S., Prat, A., Dobrolecki, L. E., Petrovic, I., Lai, Q., Landis, M. D., Wiechmann, L., Schiff, R., Giuliano, M., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-4081 · Cited by 483 · see citing works
ER stress–mediated autophagy promotes Myc-dependent transformation and tumor growth
Hart, L. S., Cunningham, J. T., Datta, T., Dey, S., Tameire, F., Lehman, S. L., Qiu, B., Zhang, H., Cerniglia, G. J., Bi, M., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci62973 · Cited by 436 · see citing works
Devaiah, B. N., Lewis, B. A., Cherman, N., Hewitt, M. C., Albrecht, B. K., Robey, P. G., Ozato, K., Sims, R. J., & Singer, D. S. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1120422109 · Cited by 379 · 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
Viswanathan, S. R., Ha, G., Hoff, A. M., Wala, J. A., Carrot-Zhang, J., Whelan, C. W., Haradhvala, N. J., Freeman, S. S., Reed, S. C., Rhoades, J., et al. (2018) · Cell · doi:10.1016/j.cell.2018.05.036 · Cited by 365 · see citing works
KinMap: a web-based tool for interactive navigation through human kinome data
Eid, S., Turk, S., Volkamer, A., Rippmann, F., & Fulle, S. (2017) · BMC Bioinformatics · doi:10.1186/s12859-016-1433-7 · Cited by 350 · 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
Dynamic phosphorylation patterns of RNA polymerase II CTD during transcription
Heidemann, M., Hintermair, C., Voß, K., & Eick, D. (2012) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2012.08.013 · Cited by 300 · 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
Niki, T., Iba, S., Tokunou, M., Yamada, T., Matsuno, Y., & Hirohashi, S. (2000) · PubMed · Cited by 288 · see citing works
Krajewska, M., Dries, R., Grassetti, A. V., Dust, S., Gao, Y., Huang, H., Sharma, B., Day, D. S., Kwiatkowski, N., Pomaville, M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09703-y · Cited by 281 · see citing works
Tian, B., Pan, Z., & Lee, J. Y. (2007) · Genome Research · doi:10.1101/gr.5532707 · Cited by 231 · see citing works
Tao, Y., Pinzi, V., Bourhis, J., & Deutsch, É. (2007) · Nature Clinical Practice Oncology · doi:10.1038/ncponc0934 · Cited by 227 · see citing works
Triple negative breast cancer - prognostic factors and survival
Ovčariček, T., Frkovic, S. G., Matos, E., Možina, B., & Borštnar, S. (2011) · Radiology and Oncology · doi:10.2478/v10019-010-0054-4 · Cited by 226 · see citing works
Joshi, P. M., Sutor, S. L., Huntoon, C. J., & Karnitz, L. M. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.551143 · Cited by 201 · 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
Menghi, F., Barthel, F. P., Yadav, V. K., Tang, M., Ji, B., Tang, Z., Carter, G. W., Ruan, Y., Scully, R., Verhaak, R. G. W., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.06.008 · Cited by 169 · see citing works
Structural and functional analysis of the Cdk13/Cyclin K complex
Greifenberg, A. K., Hönig, D., Pilarova, K., Düster, R., Bartholomeeusen, K., Bösken, C. A., Anand, K., Blazek, D., & Geyer, M. (2016) · Cell Reports · doi:10.1016/j.celrep.2015.12.025 · Cited by 157 · see citing works
Popova, T., Manié, E., Boeva, V., Battistella, A., Goundiam, O., Smith, N. K., Mueller, C. R., Raynal, V., Mariani, O., Sastre-Garau, X., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-15-2128 · Cited by 130 · see citing works
Structure of an RNA polymerase II preinitiation complex
Murakami, K., Tsai, K., Kalisman, N., Bushnell, D. A., Asturias, F. J., & Kornberg, R. D. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1518255112 · Cited by 106 · see citing works
Cdk12 is essential for embryonic development and the maintenance of genomic stability
Juan, H. U., Lin, Y.-J., Chen, H.-R., & Fann, M.-J. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2015.157 · Cited by 102 · see citing works
Bartkowiak, B., & Greenleaf, A. L. (2011) · Transcription · doi:10.4161/trns.2.3.15004 · Cited by 62 · see citing works
Genomic signatures as predictive biomarkers of homologous recombination deficiency in ovarian cancer
Vanderstichele, A., Busschaert, P., Olbrecht, S., Lambrechts, D., & Vergote, I. B. (2017) · European Journal of Cancer · doi:10.1016/j.ejca.2017.08.029 · Cited by 61 · see citing works
Lau, H. Y., Tang, J., Casey, P. J., & Wang, M. (2017) · Oncogene · doi:10.1038/onc.2016.508 · Cited by 46 · see citing works
‘Triple Negative’ Breast Cancer: a New Area for Phase III Breast Cancer Clinical Trials
Kilburn, L. S. (2008) · Clinical Oncology · doi:10.1016/j.clon.2007.09.010 · Cited by 37 · see citing works
Development of dual casein kinase 1δ/1ε (CK1δ/ε) inhibitors for treatment of breast cancer
Monastyrskyi, A., Nilchan, N., Quereda, V., Noguchi, Y., Ruiz, C. H., Grant, W. M., Cameron, M. D., Duckett, D. R., & Roush, W. R. (2017) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2017.12.020 · Cited by 32 · see citing works
Self-citationCoffee reduces KRAS expression in Caco-2 human colon carcinoma cells via regulation of miRNAs
Nakayama, T., Funakoshi‐Tago, M., & Tamura, H. (2017) · Oncology Letters · doi:10.3892/ol.2017.6227 · Cited by 27 · see citing works
E2F1 germline copy number variations and melanoma susceptibility
Rocca, M. S., Benna, C., D, S. M. M., Rossi, C. R., Msaki, A., Nisio, A. D., Opocher, G., & Foresta, C. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-1933-0 · Cited by 22 · see citing works
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“…was later found to operate through the same DDB1-dependent degrader mechanism. it has demonstrated profound anti-tumor efficacy in several preclinical models including those for breast, gastric, colorectal and skin cancers (Quereda et al. 2019; wu et al. 2021; Dai et al. 2022; Houles et al. 2023).”
- Authors
- Quereda, V., Bayle, S., Vena, F., Frydman, S. M., Monastyrskyi, A., Roush, W. R., & Duckett, D. R.
- Affiliations
- Moffitt Cancer Center (US)
- Scripps Research Institute (US)
- Corresponding author
- Duckett, Derek R.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 36
- Issue
- 5
- Pages
- 545-558.e7
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2981873089
- Cited by
- 352
- References
- 51
- Citations by year
- 2026: 42 · 2025: 46 · 2024: 57 · 2023: 69 · 2022: 53 · 2021: 51 · 2020: 32 · 2019: 2
- FWCI
- 14.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- H. Lee Moffitt Cancer Center and Research Institute
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Keywords
- CDK12, CDK13, triple-negative breast cancer, cyclin-dependent kinase inhibitors, RNA polymerase II C-terminal domain phosphorylation, intronic polyadenylation, DNA damage response, DNA repair deficiency, PARP inhibitors, DNA-damaging chemotherapy, epigenetic regulation, chromatin modifiers
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Animals, Antineoplastic Combined Chemotherapy Protocols, Cisplatin, DNA Damage, Drug Synergism, Female, Humans, Introns, Gene Expression Regulation, Neoplastic, CDC2 Protein Kinase, Cyclin-Dependent Kinases, Xenograft Model Antitumor Assays, Polyadenylation, Epigenesis, Genetic, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Homologous Recombination, Triple Negative Breast Neoplasms
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