Th e role of CDK12 in tumor bio logy
Authors:
M. Dzimková 1; J. Procházková 1; Jaroslav Klát 2; J. Kohoutek 1
Authors‘ workplace:
Oddělení chemie a toxikologie, Výzkumný ústav veterinárního lékařství, v. v. i., Brno
1; Onkogynekologické oddělení, FN Ostrava
2
Published in:
Klin Onkol 2020; 33(4): 260-267
Category:
Review
doi:
https://doi.org/10.14735/amko2020260
Overview
Background: Physiological function of cyclin-dependent kinase 12 (CDK12) is crucial for several cellular processes, including regulation of transcription, RNA splicing, transcription termination and polyadenylation. It is well documented by now that CDK12 controls transcription of the unique set of genes involved in DNA-damage response, replication of DNA and response to cellular stress. Just recently, a key function of CDK12 in the induction of tandem duplication of specific DNA sequences within the metastatic castrate resistant prostate tumors has been documented. Therefore, it is possible to recognize CDK12 as a tumor suppressor; nevertheless, there is a growing body of evidence that CDK12 can support tumor growth under specific circumstances and thus act as a tumor oncogene. CDK12 therefore represents an alternative diagnostic approach for breast, ovarian and prostate tumors, especially when conventional treatment is not active and there is a need for more effective approaches, such as concept of synthetic lethality.
Methods: The discussed scientific papers can be reached at the PubMed and Scopus databases before 1th of April 2020.
Purpose: The aim of the review is to summarize current knowledge relevant to the function of CDK12 as a tumor suppressor or oncogene in various tumors and to discuss the use of specific CDK12 inhibitors for patient treatment. At the end of the article, we discuss the potential use of CDK12 in the treatment of specific tumors by its targeted inhibition in monotherapy or in combination with poly (ADP ribose) polymerase 1 (PARP1) and checkpoint kinase 1 (CHK1) inhibitors.
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.
Keywords:
breast cancer – ovarian cancer – cyclin-dependent kinase 12 – CDK12 – PARP1 – CHK1
Sources
1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100 (1): 57–70. doi: 10.1016/s0092-8674 (00) 81683-9.
2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144 (5): 646–674. doi: 10.1016/j.cell.2011.02.013.
3. Kent LN, Leone G. The broken cycle: E2F dysfunction in cancer. Nat Rev Cancer 2019; 19 (6): 326–338. doi: 10.1038/s41568-019-0143-7.
4. Whittaker SR, Mallinger A, Workman P et al. Inhibitors of cyclin-dependent kinases as cancer therapeutics. Pharmacol Ther 2017; 173: 83–105. doi: 10.1016/j.pharmthera.2017.02.008.
5. Satyanarayana A, Kaldis P. Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms. Oncogene 2009; 28 (33): 2925–2939. doi: 10.1038/onc.2009.170.
6. Asghar U, Witkiewicz AK, Turner NC et al. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 2015; 14 (2): 130–146. doi: 10.1038/nrd4504.
7. Bruyere C, Meijer L. Targeting cyclin-dependent kinases in anti-neoplastic therapy. Curr Opin Cell Biol 2013; 25 (6): 772–779. doi: 10.1016/j.ceb.2013.08.004.
8. Chirackal Manavalan AP, Pilarova K, Kluge M et al. CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes. EMBO Rep 2019; 20 (9): e47592. doi: 10.15252/embr.201847592.
9. Kohoutek J, Blazek D. Cyclin K goes with Cdk12 and Cdk13. Cell Div 2012; 7: 12. doi: 10.1186/1747-1028-7-12.
10. Greenleaf AL. Human CDK12 and CDK13, multi-tasking CTD kinases for the new millenium. Transcription 2019; 10 (2): 91–110. doi: 10.1080/21541264.2018.1535211
11. Malumbres M. Cyclin-dependent kinases. Genome Biol 2014; 15 (6): 122. doi: 10.1186/gb4184.
12. Hydbring P, Malumbres M, Sicinski P. Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases. Nature Reviews Molecular Cell Biology 2016; 17 (5): 280–292. doi: 10.1038/nrm.2016.27.
13. Kohoutek J. P-TEFb – the final frontier. Cell Div 2009; 4: 19. doi: 10.1186/1747-1028-4-19.
14. Malumbres M, Harlow E, Hunt T et al. Cyclin-dependent kinases: a family portrait. Nat Cell Biol 2009; 11 (11): 1275–1276. doi: 10.1038/ncb1109-1275.
15. Eick D, Geyer M. The RNA polymerase ii carboxy-terminal domain (CTD) code. Chemical Reviews 2013; 113 (11): 8456–8490. doi: 10.1021/cr400071f.
16. Jeronimo C, Bataille AR, Robert F. The writers, readers, and functions of the RNA polymerase II C-terminal domain code. Chemical Reviews 2013; 113 (11): 8491–8522. doi: 10.1021/cr4001397.
17. Bradner JE, Hnisz D, Young RA. Transcriptional addiction in cancer. Cell 2017; 168 (4): 629–643. doi: 10.1016/j.cell.2016.12.013.
18. Ko TK, Kelly E, Pines S. CrkRS: a novel conserved Cdc2-related protein kinase that colocalises with SC35 speckles. J Cell Sci 2001; 114 (Pt 14): 2591–2603.
19. Blazek D, Kohoutek J, Bartholomeeusen K et al. The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes Dev 2011; 25 (20): 2158–2172. doi: 10.1101/gad.16962311.
20. Juan HC, Lin Y, Chen HR et al. Cdk12 is essential for embryonic development and the maintenance of genomic stability. Cell Death Differ 2016; 23 (6): 1038–1048. doi: 10.1038/cdd.2015.157.
21. Blazek D. The cyclin K/Cdk12 complex: an emerging new player in the maintenance of genome stability. Cell Cycle 2012; 11 (6): 1049–1050. doi: 10.4161/cc.11.6.19678.
22. Davidson L, Muniz L, West S. 3‘ end formation of pre-mRNA and phosphorylation of Ser2 on the RNA polymerase II CTD are reciprocally coupled in human cells. Genes Dev 2014; 28 (4): 342–356. doi: 10.1101/gad.231274.113.
23. Eifler TT, Shao W, Bartholomeeusen K et al. Cyclin-dependent kinase 12 increases 3‘ end processing of growth factor-induced c-FOS transcripts. Mol Cell Biol 2015; 35 (2): 468–478. doi: 10.1128/MCB.01157-14.
24. Cheng SW, Kuzyk MA, Moradian A et al. Interaction of cyclin-dependent kinase 12/CrkRS with cyclin K1 is required for the phosphorylation of the C-terminal domain of RNA polymerase II. Mol Cell Biol 2012; 32 (22): 4691–4704. doi: 10.1128/MCB.06267-11.
25. Liang K, Gao X, Gilmore JM et al. Characterization of human cyclin-dependent kinase 12 (CDK12) and CDK13 complexes in C-terminal domain phosphorylation, gene transcription, and RNA processing. Mol Cell Biol 2015; 35 (6): 928–938. doi: 10.1128/MCB.01426-14.
26. Tien JF, Mazloomian A, Cheng SG et al. CDK12 regulates alternative last exon mRNA splicing and promotes breast cancer cell invasion. Nucleic Acids Res 2017; 45 (11): 6698–6716. doi: 10.1093/nar/gkx187.
27. Zhang T, Kwiatkowski N, Olson CM et al. Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat Chem Biol 2016; 12 (10): 876–884. doi: 10.1038/nchembio.2166.
28. Johnson SF, Cruz C, Greifenberg AK et al. CDK12 inhibition reverses de novo and acquired PARP inhibitor Rresistance in BRCA wild-type and mutated models of triple-negative breast cancer. Cell Rep 2016; 17 (9): 2367–2381. doi: 10.1016/j.celrep.2016.10.077.
29. Ekumi KM, Paculova H, Lenasi T et al. Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex. Nucleic Acids Res 2015; 43 (5): 2575–2589. doi: 10.1093/nar/gkv101.
30. Dubbury SJ, Boutz PL, Sharp PA. CDK12 regulates DNA repair genes by suppressing intronic polyadenylation. Nature 2018; 564 (7734): 141–145. doi: 10.1038/s41586-018-0758-y.
31. Wang C, Wang H, Lieftink C et al. CDK12 inhibition mediates DNA damage and is synergistic with sorafenib treatment in hepatocellular carcinoma. Gut 2020; 69 (4): 727-736. doi: 10.1136/gutjnl-2019-318506.
32. Bajrami I, Frankum JR, Konde A et al. Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity. Cancer Res 2014; 74 (1): 287–297. doi: 10.1158/0008-5472.CAN-13-2541.
33. Joshi PM, Sutor SL, Huntoon CJ et al. Ovarian cancer-associated mutations disable catalytic activity of CDK12, a kinase that promotes homologous recombination repair and resistance to cisplatin and poly (ADP-ribose) polymerase inhibitors. J Biol Chem 2014; 289 (13): 9247–9253. doi: 10.1074/jbc.M114.551143.
34. Paculova H, Kramara J, Simeckova S et al. BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors. Tumour Biol 2017; 39 (10) doi: 1010428317727479. doi: 10.1177/1010428317727479.
35. Lei T, Zhang P, Zhang X et al. Cyclin K regulates prereplicative complex assembly to promote mammalian cell proliferation. Nat Commun 2018; 9 (1): 1876. doi: 10.1038/s41467-018-04258-w.
36. Li X, Chatterjee N, Spirohn K e al. Cdk12 is a gene-selective RNA polymerase II kinase that regulates a subset of the transcriptome, including Nrf2 target genes. Sci Rep 2016; 6: 21455. doi: 10.1038/srep21455.
37. Quereda V, Bayle S, Vena S et al. Therapeutic targeting of CDK12/CDK13 in triple-negative breast cancer. Cancer Cell 2019; 36 (5): 545–558. doi: 10.1016/j.ccell.2019.09.004.
38. Marshall CH, Imada EL, Tang Z et al. CDK12 inactivation across solid tumors: an actionable genetic subtype. Oncoscience 2019; 6 (5-6): 312–316. doi: 10.18632/oncoscience.481.
39. Biswas R, Gao S, Cultraro CM et al. Genomic profiling of multiple sequentially acquired tumor metastatic sites from an „exceptional responder“ lung adenocarcinoma patient reveals extensive genomic heterogeneity and novel somatic variants driving treatment response. Cold Spring Harb Mol Case Stud 2016; 2 (6): a001263. doi: 10.1101/mcs.a001263.
40. Zhang X, Nguyen KD, Rudnick PA et al. Quantitative mass spectrometry to interrogate proteomic heterogeneity in metastatic lung adenocarcinoma and validate a novel somatic mutation CDK12-G879V. Mol Cell Proteomics 2019; 18 (4): 622–641. doi: 10.1074/mcp.RA118.001266.
41. Geyer JT, Subramaniyam S, Jiang Y et al. Lymphoblastic transformation of follicular lymphoma: a clinicopathologic and molecular analysis of 7 patients. Hum Pathol 2015; 46 (2): 260–271. doi: 10.1016/j.humpath.2014.10.021.
42. Riches JC, Schultz N, Ku GY et al. Genomic profiling of esophagogastric (EG) tumors in clinical practice. J Clin Oncol 2015; 33 (3_suppl): 57–57.
43. Cancer Genome Atlas Research. Integrated genomic analyses of ovarian carcinoma. Nature 2011; 474 (7353): 609–615. doi: 10.1038/nature10166.
44. Carter SL, Cibulskis, K, Helman E et al. Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol 2012; 30 (5): 413–421. doi: 10.1038/nbt.2203.
45. Quigley D A, Dang HX, Zhao SG et al. Genomic hallmarks and structural variation in metastatic prostate cancer. Cell 2018; 174 (3): 758–769. doi: 10.1016/j.cell.2018.06.039.
46. Viswanathan SR, Ha G, Hoff AM et al. Structural alterations driving castration-resistant prostate cancer revealed by linked-read genome sequencing. Cell 2018; 174 (2): 433–447. doi: 10.1016/j.cell.2018.05.036.
47. Wu YM, Cieslik, M, Lonigro RJ et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. Cell 2018; 173 (7): 1770–1782. doi: 10.1016/j.cell.2018.04.034.
48. Manogue C, Cotogno P, Ledet E et al. Biomarkers for Programmed Death-1 inhibition in prostate cancer. The Oncologist 2019; 24 (4): 444–448. doi: 10.1634/theoncologist.2018-0546.
49. Menghi F, Barthel FP, Yadav V et al. The tandem duplicator phenotype is a prevalent genome-wide cancer configuration driven by distinct gene mutations. Cancer Cell 2018; 34 (2): 197–210. doi: 10.1016/j.ccell.2018.06.008.
50. Cancer Genome Atlas. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490 (7418): 61–70. doi: 10.1038/nature11412.
51. Shah SP, Roth A, Goya R et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 2012; 486 (7403): 395–399. doi: 10.1038/nature10933.
52. Kauraniemi P, Kallioniemi A. Activation of multiple cancer-associated genes at the ERBB2 amplicon in breast cancer. Endocr Relat Cancer 2006; 13 (1): 39–49. doi: 10.1677/erc.1.01147.
53. Mertins P, Mani DR, Ruggles KV et al. Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 2016; 534 (7605): 55–62. doi: 10.1038/nature18003.
54. Sircoulomb F, Bekhouche I, Finetti P et al. Genome profiling of ERBB2-amplified breast cancers. BMC Cancer 2010; 10: 539. doi: 10.1186/1471-2407-10-539.
55. Capra M, Nuciforo PG, Confalonieri S et al. Frequent alterations in the expression of serine/threonine kinases in human cancers. Cancer Res 2006; 66 (16): 8147–8154. doi: 10.1158/0008-5472.CAN-05-3489.
56. Zhou C, Feng X, Yuan F et al. Difference of molecular alterations in HER2-positive and HER2-negative gastric cancers by whole-genome sequencing analysis. Cancer Manag Res 2018; 10: 3945–3954. doi: 10.2147/CMAR.S172710.
57. Chen K, Quan J, Yang J et al. The potential markers of endocrine resistance among HR+ /HER2+ breast cancer patients. Clin Transl Oncol 2020; 22 (4): 576–584. doi: 10.1007/s12094-019-02163-2.
58. Naidoo K, Wai PT, Maguire SL et al. Evaluation of CDK12 protein expression as a potential novel biomarker for DNA damage response-targeted therapies in breast cancer. Mol Cancer Ther 2018; 17 (1): 306–315. doi: 10.1158/1535-7163.MCT-17-0760.
59. Natrajan R, Wilkerson PM, Marchio C et al. Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast. J Pathol 2014; 232 (5): 553–565. doi: 10.1002/path.4325.
60. Chen B, Zhang G, Wei G et al. Heterogeneity of genomic profile in patients with HER2-positive breast cancer. Endocr Relat Cancer 2020; 27 (3): 153–162. doi: 10.1530/ERC-19-0414.
61. Iorns E, Martens-De Kemp SR, Lord CJ et al. Ashworth CRK7 modifies the MAPK pathway and influences the response to endocrine therapy. Carcinogenesis 2009; 30 (10): 1696–1701. doi: 10.1093/carcin/bgp187.
62. Paruch K, Dwyer MP, Alvarez C et al. Discovery of dinaciclib (SCH 727965): A potent and selective inhibitor of cyclin-dependent kinases. ACS Med Chem Lett 2010; 1 (5): 204–208. doi: 10.1021/ml100051d.
63. Geng M, Yang Y, Cao X et al. Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma. Biochem Biophys Res Commun 2019; 520 (3): 544–550. doi: 10.1016/j.bbrc.2019.10.052.
64. Toyoshima M, Howie HL, Imakura M et al. Functional genomics identifies therapeutic targets for MYC-driven cancer. Proc Natl Acad Sci U S A 2012; 109 (24): 9545–9550. doi: 10.1073/pnas.1121119109.
65. May WA, Lessnick SL, Braun BS et al. The Ewing‘s sarcoma EWS/FLI-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1. Mol Cell Biol 1993; 13 (12): 7393–7398. doi: 10.1128/mcb.13.12.7393.
66. Iniguez AB, Stolte B, Wang EJ et al. EWS/FLI confers tumor cell synthetic lethality to CDK12 inhibition in Ewing sarcoma. Cancer Cell 2018; 33 (2): 202–216. doi: 10.1016/j.ccell.2017.12.009.
67. Rusan M, Li K, Li Y et al. Suppression of adaptive responses to targeted cancer therapy by transcriptional repression. Cancer Discov 2018; 8 (1): 59–73. doi: 10.1158/2159-8290.CD-17-0461.
68. Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature 2012; 481 (7381): 287–294. doi: 10.1038/nature10760.
69. Bryant HE, Schultz N, Thomas HD et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly (ADP-ribose) polymerase. Nature 2005; 434 (7035): 913–917. doi: 10.1038/nature03443.
70. Helleday T, Bryant HE, Schultz N. Poly (ADP-ribose) polymerase (PARP-1) in homologous recombination and as a target for cancer therapy. Cell Cycle 2005; 4 (9): 1176–1178. doi: 10.4161/cc.4.9.2031.
71. Montoni A, Robu M, Pouliot E et al. Resistance to PARP-inhibitors in cancer therapy. Front Pharmacol 2013; 4: 18. doi: 10.3389/fphar.2013.00018.
72. Noordermeer SM, Van Attikum H. PARP inhibitor resistance: A tug-of-war in BRCA-mutated cells. Trends Cell Biol 2019; 29 (10): 820–834. doi: 10.1016/j.tcb.2019.07.
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Paediatric clinical oncology Surgery Clinical oncologyArticle was published in
Clinical Oncology
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