Cdk12-KO Mouse

Cyclin-dependent kinase 12 (Cdk12) is a member of the CDK family of serine/threonine protein kinases, which associates with cyclin K to exert its functions [5]. It is crucial in regulating gene transcription, mRNA processing, and translation, and plays a significant role in diverse biological processes such as cell cycle progression, cell proliferation, and DNA damage response (DDR) [1,2,5].

In prostate cancer, biallelic loss of Cdk12 defines a metastatic castration-resistant prostate cancer (mCRPC) subtype. Cdk12 ablation in murine prostate epithelium can induce preneoplastic lesions with lymphocytic infiltration, and concurrent Cdk12/Trp53 ablation promotes proliferation of prostate-derived organoids. Also, Cdk12-mutant organoids and patient-derived xenografts are sensitive to inhibition or degradation of the paralog kinase, CDK13 [4]. In triple-negative breast cancer, inhibition or loss of Cdk12/CDK13 triggers intronic polyadenylation site cleavage that suppresses the expression of core DNA damage response proteins, leading to a "BRCAness" phenotype [3].

In conclusion, Cdk12 is essential for multiple biological functions including gene regulation and cell-cycle-related processes. The gene knockout (KO) and conditional knockout (CKO) mouse models have been instrumental in revealing its role in prostate and breast cancers, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Emadi, Fatemeh, Teo, Theodosia, Rahaman, Muhammed H, Wang, Shudong. 2020. CDK12: a potential therapeutic target in cancer. In Drug discovery today, 25, 2257-2267. doi:10.1016/j.drudis.2020.09.035. https://pubmed.ncbi.nlm.nih.gov/33038524/

2. Liang, Shujing, Hu, Lifang, Wu, Zixiang, Xu, Xia, Qian, Airong. 2020. CDK12: A Potent Target and Biomarker for Human Cancer Therapy. In Cells, 9, . doi:10.3390/cells9061483. https://pubmed.ncbi.nlm.nih.gov/32570740/

3. Quereda, Victor, Bayle, Simon, Vena, Francesca, Roush, William R, Duckett, Derek R. 2019. Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer. In Cancer cell, 36, 545-558.e7. doi:10.1016/j.ccell.2019.09.004. https://pubmed.ncbi.nlm.nih.gov/31668947/

4. Tien, Jean Ching-Yi, Luo, Jie, Chang, Yu, Ding, Ke, Chinnaiyan, Arul M. 2024. CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13. In Cell reports. Medicine, 5, 101758. doi:10.1016/j.xcrm.2024.101758. https://pubmed.ncbi.nlm.nih.gov/39368479/

5. Tang, Ruijun, Liu, Jing, Li, Shuyao, Yuan, Kai, Shao, Hao. 2022. A patent and literature review of CDK12 inhibitors. In Expert opinion on therapeutic patents, 32, 1055-1065. doi:10.1080/13543776.2022.2126765. https://pubmed.ncbi.nlm.nih.gov/36120913/