Therapeutic targeting of CDK7 in prostate cancer

Dysregulation in transcriptional programs, most notably androgen receptor (AR) signalling, cell proliferation, DNA replication, and DNA repair, are hallmarks of castration-resistant prostate cancer, which kills over 11,000 men per year in the UK alone. Cyclin dependent kinase 7 (CDK7) has a pivotal role in transcription regulation, androgen receptor signalling, and cell cycle control and has emerged as a promising therapeutic target for this disease. Specifically, as part of the general transcription factor TFIIH, CDK7 activity is required for RNA polymerase II-mediated transcription initiation, promoter clearance and transcript elongation. Moreover, CDK7 has been shown to directly phosphorylate AR at serine 515, with this post-translational modification being required for optimal directed ubiquitination, proteasomal degradation and cyclical recruitment of AR to gene promoters. CDK7 has also been reported to mediate the interaction of AR with its transcriptional co-activator MED1, facilitating oncogenic AR transcription in prostate cancer. In addition to these transcriptional roles, CDK7 activity directs cell cycle transitions by phosphorylating threonine 160 in the T-loop of cell cycle CDKs (CDK1, CDK2, CDK4, and CDK6), allowing cancer cells to proliferate.

Using CT7001 (formerly ICEC0942), a selective non-covalent CDK7 inhibitor, the goal of the project is to investigate CDK7 inhibition as a treatment strategy in prostate cancer. The aims for this are three-fold: (1) to study the effect of CDK7 inhibition by CT7001 on prostate cancer cell growth using well-established in vitro (cell lines), in vivo (mouse xenografts studies) and ex vivo (patient tumour explants) models of the disease; (2) to investigate the mechanism of action of CT7001 in prostate cancer, including exploring the effects of treatment on RNA polymerase II-mediated gene transcription, cell cycle progression, and androgen receptor signalling in both castration-sensitive and castration-resistant models of prostate cancer (primarily in vitro); (3) in addition to elucidating the role of CDK7 activity in prostate cancer, the mechanistic investigations in aim (2) also harbour the potential to uncover transcription regulatory proteins that are promising drug targets for novel prostate cancer therapeutics - aim (3) of the project is to validate these targets using in vitro models of prostate cancer.

This project will validate CDK7 inhibition as a therapeutic strategy for prostate cancer and will enable key investigations into the mechanism of action of CT7001. This may reveal novel targets for the treatment of this disease and may identify potential vulnerabilities to exploit in co-treatment strategies. Since the clinical development of CDK7-targeted anticancer therapies is still in early stages, these results may highlight considerable opportunities for the treatment of other cancers with CDK7 inhibitors, particularly those with similar transcriptional and cell cycling dysregulations.