Current strategies to inhibit 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, providing a rationale for its therapeutic targeting in CRPC.
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 mechanisms driving CT7001 activity, alone and in combination with the antiandrogen enzalutamide.
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.
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.
British journal of cancer. 2023 Apr 19 [Epub ahead of print]
Theodora A Constantin, Anabel Varela-Carver, Kyle K Greenland, Gilberto Serrano de Almeida, Ellen Olden, Lucy Penfold, Simon Ang, Alice Ormrod, Damien A Leach, Chun-Fui Lai, Edward K Ainscow, Ash K Bahl, David Carling, Matthew J Fuchter, Simak Ali, Charlotte L Bevan
Imperial Centre for Translational and Experimental Medicine, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK., MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital, London, UK., Carrick Therapeutics, Nova UCD, Bellfield Innovation Park, Dublin, 4, Ireland., Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, White City Campus, London, UK., Imperial Centre for Translational and Experimental Medicine, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK. .