Transcription associated cyclin-dependent kinases as therapeutic targets for prostate cancer

Abstract

Transcriptional deregulation has emerged as a hallmark of several cancer types. In metastatic castration-resistant prostate cancer, a stage in which systemic androgen deprivation therapies fail to show clinical benefit, transcriptional addiction to the androgen receptor is maintained in most patients. This has led to increased efforts to find novel therapies that prevent oncogenic transactivation of the androgen receptor. In this context, a group of druggable protein kinases, known as transcription associated cyclin-dependent kinases (tCDKs), show great potential as therapeutic targets. Despite initial reservations about targeting tCDKs due to their ubiquitous and prerequisite nature, preclinical studies showed that selectively inhibiting such kinases could provide sufficient therapeutic window to exert antitumour effects in the absence of systemic toxicity. As a result, several highly specific inhibitors are currently being trialled in solid tumours, including prostate cancer. This article summarises the roles of tCDKs in regulating gene transcription and highlights rationales for their targeting in prostate cancer. It provides an overview of the most recent developments in this therapeutic area, including the most recent clinical advances, and discusses the utility of tCDK inhibitors in combination with established cancer agents.

Fig. 1. Transcription associated CDKs and their roles in regulating RNA polymerase II (Pol II) during eukaryotic transcription.

The Pol II transcription cycle can be divided into four main sequential steps. Initiation begins with the assembly of the preinitiation complex, including Pol II and basal transcription factors (TF), and binding of CDK8/Mediator complex, which anchors the preinitiation complex to gene-specific upstream enhancers. Promoter escape is facilitated by the phosphorylation of the Pol II C-terminal domain (CTD) at serine 5 (Ser5) and serine 7 (Ser7) by CDK7, which promotes recruitment of pre-mRNA 5′capping enzymes. Transcription is provisionally paused downstream of the transcription start site by the association of two negative factors, DRB sensitivity-inducing factor (DSIF) and negative elongation factor (NELF). Bromodomain-containing protein 4 (BRD4) and the positive transcription elongation factor (P-TEFb), consisting of CDK9 and cyclin T, are recruited to acetylated chromatin. CDK7 activates CDK9 through T-loop phosphorylation, which in turn mediates promoter-proximal pause release by phosphorylating DSIF, NELF, and the Pol II CTD at serine 2 (Ser2). Progression from the transcriptional start site (TSS) across the gene body and productive elongation are maintained by the differential phosphorylation of the Pol II CTD at Ser2, Ser5, and Ser7 by CDK9 and CDK12/CDK13. The pattern of CTD phosphorylation contributes to the recruitment of splicing and chromatin remodelling factors. Termination is regulated by CDK12 which promotes the use of distal 3′ transcription termination sites and recruitment of cleavage and polyadenylation (Poly A) factors. The graph underneath depicts relative abundance of Pol II Ser-CTD modifications across protein-coding genes, determined by chromatin immunoprecipitation (ChIP)-seq investigations. Created with BioRender.com.

Fig. 2. The role of transcription associated CDKs (tCDKs) in regulating the transcriptional activity of the androgen receptor (AR).

(Top) CDK7 phosphorylates MED1 at threonine 1457 (Thr1457) and promotes association of the Mediator complex with AR and the transcription machinery. Phosphorylation of chromatin-bound AR at serine 81 (Ser81) by CDK9 enhances recruitment of co-activators and strongly promotes transcription of AR target genes. (Bottom left) CDK7 directly phosphorylates AR at serine 515 (Ser515), which directs efficient recycling of the receptor for cyclical gene activation. (Bottom right) Phosphorylation of AR at serine 308 (Ser308) by CDK11 leads to transcriptional repression through increased recruitment of AR co-repressors. Created with BioRender.com.

Fig. 3. Potential combination strategies with transcription associated CDK inhibitors (CDKi) for the treatment of advanced malignancies.

PD-1, programmed cell death protein 1; CAR, chimeric antigen receptor; PARP, poly (ADP-ribose) polymerase; BET, bromodomain and extra-terminal motif; HDAC, histone deactylase; EGFR, epidermal growth factor receptor. Created with BioRender.com.