ABSTRACT
Background Current strategies to inhibit the androgen receptor (AR) are circumvented in castration-resistant prostate cancer (CRPC). Cyclin-dependent kinase 7 (CDK7) promotes AR signalling, in addition to established roles in cell cycle and global transcription regulation, together, providing a rationale for its therapeutic targeting in CRPC.
Methods The antitumour activity of CT7001, an orally bioavailable CDK7 inhibitor, was investigated across CRPC models in vitro and in xenograft models in vivo. Cell-based assays and transcriptomic analyses of treated xenografts were employed to investigate the mechanism driving activity of CT7001, alone and in combination with the antiandrogen enzalutamide.
Results CT7001 selectively engages with CDK7 in prostate cancer cells, causing inhibition of proliferation and cell cycle arrest. Activation of p53, induction of apoptosis, and suppression of transcription mediated by full-length and constitutively active AR splice variants contribute to antitumour efficacy in vitro. Oral administration of CT7001 represses growth of CRPC xenografts and significantly augments growth inhibition achieved by enzalutamide. Transcriptome analyses of treated xenografts indicate cell cycle and AR inhibition as the mode of action of CT7001 in vivo.
Conclusions This study supports CDK7 inhibition as a strategy to target deregulated cell proliferation and demonstrates CT7001 is a promising CRPC therapeutic, alone or in combination with AR-targeting compounds.
Competing Interest Statement
G.S.A. has previously been supported by a research grant from Carrick Therapeutics Ltd to C.L.B. S. Ali is a named inventor on CDK7 inhibitor patents that have been licensed to Carrick Therapeutics Ltd, has received royalty payments, shares, and research funding from Carrick Therapeutics. M.J.F. is a named inventor on CDK7 inhibitor patents that have been licensed to Carrick Therapeutics Ltd and has received royalty payments from Carrick Therapeutics. A.K.B. and E.C. are/were at the time of this study employees of Carrick Therapeutics. The following authors declare that they have no competing interests: T.A.C., A.V.C., K.K.G., L.P., S. Ang, A.O., D.C..
LIST OF ABBREVIATIONS
- AR
- androgen receptor
- AR-V
- androgen receptor variant
- AST
- aspartate aminotransferase
- CAK
- CDK-activating kinase
- CDK
- cyclin-dependent kinase
- CeTSA
- cellular thermal shift assay
- CRPC
- castration-resistant prostate cancer
- CTD
- C-terminal domain
- DMSO
- dimethylsulfoxide
- FCS
- foetal calf serum
- FDR
- false discovery rate
- FL-AR
- full-length androgen receptor
- GR
- growth-rate
- GSEA
- gene set enrichment analysis
- LBD
- ligand-binding domain
- Padj
- adjusted p-value
- PBS
- phosphate buffered saline
- PCA
- principal component analysis
- PolII
- RNA polymerase II
- PSA
- prostate-specific antigen
- P-TEFb
- positive transcription elongation factor b
- Rb
- retinoblastoma
- RT-qPCR
- quantitative reverse transcription PCR
- SRB
- sulforhodamine B