The Potential Use of CDK7 Inhibitors to Treat Metastatic Castration-Resistant Prostate Cancer via Reduction in MED1 Phosphorylation and Androgen Receptor Signaling.
Background: Prostate cancer (PC) is the most common malignancy in men. 1,2 PC begins with mutations in prostatic ductal epithelial cells, which produce androgen receptor (AR), a transcriptional regulator for genes controlling cell homeostasis. 1 These mutations increase AR signaling, driving tumorigenesis and metastasis. 2 Eventual progression to metastatic PC generates the deadly complications of the disease. 2 If diagnosed early, localized PC is commonly treated with androgen deprivation therapy (ADT), which involves surgical castration or drugs targeting the AR signaling pathway. 2 However, ADT leads to the development of AR-variants (AR-Vs), mutants that can signal through the AR axis in the absence of androgen. 1 This causes progression to metastatic castration resistant prostate cancer (mCRPC), an aggressive and currently incurable form of the disease. 1 Although there are many current therapies for mCRPC, these drugs only provide mild prolongation of survival, and there is a need for new and more effective treatments. 3 Given its close association with AR and the transcriptional regulator Mediator Complex 1 (MED1), Cyclin-dependent kinase 7 (CDK7) could be a promising target for mCRPC therapy. 4
Objective: In this review, we aimed to investigate the mechanism by which CDK7 drives pMED1 interaction with AR to promote pro-tumorigenic transcription in PC and to explore the efficacy of CDK7 inhibitors in the treatment of mCRPC.
Search Methods: An online search was conducted in the PubMed database for articles from 2017 to 2023 using the keywords “prostate cancer”, “CDK7”, “AR”, and “MED1”.
Results: The expression of CDK7 and pMED1 is increased in PC cells, and their expression is correlated, suggesting co-expression. 4 AR expression is correlated to both CDK7 and pMED1 expression, and CDK7/pMED1 co-expression. 4 Androgen stimulation of PC cells causes phosphorylation of MED1 at T1457, allowing it to associate with AR at super-enhancer (SE) regions and activate AR-mediated transcription. 5 AR-rich nuclear foci are formed at SE regions in PC cells, and foci formation is correlated to transcriptional activity. 6 AR, pMED1, and RNA Polymerase II interact at AR foci and pMED1 is required for foci formation. 6 AR-Vs have a unique transcription profile in mCRPC, specifically ubiquitin-conjugating enzyme E2C (UBE2C), an oncogene that activates the M-phase checkpoint of the cell cycle. 7,8 pMED1 is required for AR-V-mediated UBE2C transcription, driving mCRPC proliferation in the absence of androgen. 7 CDK7 is responsible for phosphorylation of MED1 at T1457. 5 THZ1, a CDK7 inhibitor, inhibits pMED1/AR recruitment to SE regions and decreases AR foci formation. 5, 6 THZ1 decreases pMED1 levels, induces apoptosis, and halts mCRPC progression both in vitro and in vivo in mouse models. 5 Co-administration of a CDK9 inhibitor enhances the efficacy of CDK7 inhibitors in mCRPC in vitro. 9
Conclusions: CDK7-mediated phosphorylation of MED1 drives its interaction with both AR and AR-V, increasing transcription and driving PC progression. The experimental efficacy of THZ1 in halting mCRPC progression points to the need for human clinical trials with CDK7 inhibitors, as well as future studies investigating potential combination therapies.
- Rebello RJ, Oing C, Knudsen KE, et al. Prostate cancer. National Reviews Disease Primers. 2021 Feb 4;7(1):9. doi: 10.1038/s41572-020-00243-0. PMID: 33542230.
- Wang G, Zhao D, Spring DJ, et al. Genetics and biology of prostate cancer. Genes and Development. 2018 Sep 1;32(17-18):1105-1140. doi: 10.1101/gad.315739.118. PMID: 30181359; PMCID: PMC6120714.
- Komura K, Sweeney CJ, Inamoto T, et al. Current treatment strategies for advanced prostate cancer. International Journal of Urology. 2018 Mar;25(3):220-231. doi: 10.1111/iju.13512. Epub 2017 Dec 20. PMID: 29266472; PMCID: PMC6053280.
- Paulsen FO, Kang D, Becker F, et al. Targeting cyclin-dependent kinase 7-association between CDK7 and pMED1 expression in prostate cancer tissue. Carcinogenesis. 2022;43(8):779-786. doi:10.1093/carcin/bgac036
- Rasool RU, Natesan R, Deng Q, et al. CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation. Cancer Discov. 2019;9(11):1538-1555. doi:10.1158/2159-8290.CD-19-0189.
- Zhang F, Biswas M, Massah S, et al. Dynamic phase separation of the androgen receptor and its coactivators key to regulate gene expression. Nucleic Acids Res. 2023;51(1):99-116. doi:10.1093/nar/gkac1158
- Liu G, Sprenger C, Wu PJ, et al. MED1 mediates androgen receptor splice variant induced gene expression in the absence of ligand. Oncotarget. 2018;6(1):288-304. doi:10.18632/oncotarget.2672
- Lin J, Raoof DA, Wang Z, Lin MY, Thomas DG, Greenson JK, Giordano TJ, Orringer MB, Chang AC, Beer DG, Lin L. Expression and effect of inhibition of the ubiquitin-conjugating enzyme E2C on esophageal adenocarcinoma. Neoplasia. 2006; 8:1062–1071.
- Pallasaho S, Gondane A, Kuivalainen A, et al. Castration-resistant prostate cancer cells are dependent on the high activity of CDK7 [published online ahead of print, 2022 Nov 18]. J Cancer Res Clin Oncol. 2022;10.1007/s00432-022-04475-3. doi:10.1007/s00432-022-04475-3