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Review
. 2018 Nov;71(11):957-962.
doi: 10.1136/jclinpath-2018-205356. Epub 2018 Aug 13.

CDK12: An Emerging Therapeutic Target for Cancer

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Free PMC article
Review

CDK12: An Emerging Therapeutic Target for Cancer

Goldie Y L Lui et al. J Clin Pathol. .
Free PMC article

Abstract

Cyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases that regulate transcriptional and post-transcriptional processes, thereby modulating multiple cellular functions. Early studies characterised CDK12 as a transcriptional CDK that complexes with cyclin K to mediate gene transcription by phosphorylating RNA polymerase II. CDK12 has been demonstrated to specifically upregulate the expression of genes involved in response to DNA damage, stress and heat shock. More recent studies have implicated CDK12 in regulating mRNA splicing, 3' end processing, pre-replication complex assembly and genomic stability during embryonic development. Genomic alterations in CDK12 have been detected in oesophageal, stomach, breast, endometrial, uterine, ovarian, bladder, colorectal and pancreatic cancers, ranging from 5% to 15% of sequenced cases. An increasing number of studies point to CDK12 inhibition as an effective strategy to inhibit tumour growth, and synthetic lethal interactions have been described with MYC, EWS/FLI and PARP/CHK1 inhibition. Herein, we discuss the present literature on CDK12 in cell function and human cancer, highlighting important roles for CDK12 as a clinical biomarker for treatment response and potential as an effective therapeutic target.

Keywords: C-MYC oncogene; breast cancer; cancer genetics; cell biology; ovarian cancer.

Conflict of interest statement

Competing interests: CG and CJK are cofounders of and have ownership interests in SEngine Precision Medicine. GYLL has no competing interests to declare.

Figures

Figure 1.
Figure 1.
Schematic structures of the CDK12 and CDK13 genes and chromosomal location of the respective genes. RS = arginine/serine rich motifs; PRM = proline rich motifs; KD = kinase domain.
Figure 2.
Figure 2.
Known functions of CDK12. (A) CDK12 phosphorylates RNA polymerase II (RNA Pol II) at Ser2, which promotes transcriptional elongation. (B) CDK12 interacts with RNA-processing factors to regulate splicing. (C) CDK12-mediated phosphorylation of RNA Pol II couples transcription and mRNA 3’ end processing. CDK12 reportedly regulates the expression of a distinct subset of genes, including those involved in the DNA damage response, cellular stress, and heat shock.
Figure 3.
Figure 3.
Genomic alterations of the CDK12 gene across The Cancer Genome Atlas (TCGA). Data downloaded from TCGA Provisional data sets on cBioportal (http://www.cbioportal.org/) in May 2018.
Figure 4.
Figure 4.
Potential for clinical use of CDK12 as a biomarker and/or therapeutic target. (A) CDK12 mutations that confer loss of function have been reported to promote genomic instability, rendering cancer cells more susceptible to PARP/CHK inhibitors. (B) On the other hand, CDK12 mutations that cause gain of function (e.g. amplification) could theoretically potentiate cancer cell survival by promoting expression of DNA damage repair genes. Though there are currently few reports of this, such a situation would enable use of CDK12 as a biomarker of drug response/clinical outcome, or as a drug target. (C) In cases where CDK12 is not necessarily mutated, CDK12 can enable tumor progression driven by genes such as MYC and EWS/FLI. These synthetic lethal interactions also provide an opportunity for therapeutic targeting.

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