Androgen deprivation therapy (ADT) is the gold standard treatment for metastatic prostate cancer. ADT impedes activation of the androgen receptor (AR), which drives tumour growth in most patients. Although initially effective, resistance to ADT universally emerges to promote AR activation in low/no androgen conditions. This results in lethal castration-resistant prostate cancer (CRPC), highlighting a need for novel therapeutic interventions.
Cyclin-dependent kinase (CDK) 7 is increasingly recognised as a cancer drug target due to its dual regulatory role in cell cycling and transcription. Recently, CDK7 has been reported to promote oncogenic AR signalling, indicating potential as a targetable kinase in CRPC. Here, I explore the antitumour activity of CT7001 (samuraciclib), a novel orally bioavailable inhibitor of CDK7, across CRPC models in vitro and in xenograft models in vivo. Multiple 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 AR antagonist enzalutamide.
The data presented here demonstrate that CT7001 engages with CDK7 in a selective manner to potently inhibit prostate cancer cell growth. CT7001 targets proliferation pathways, induces p53 activation and promotes apoptosis in vitro. In addition, CT7001 treatment downregulates AR transcription, and this activity is maintained in several scenarios modelling AR reactivation in CRPC. The multifaceted mode of action of CT7001 drives combinatorial activity with enzalutamide in a xenograft model of advanced CRPC.
This work supports CDK7 inhibition as a therapeutic strategy for CRPC and provides a rationale for combination regimens with ADT. This study may have clinical significance as CT7001 had acceptable safety profile and demonstrated initial efficacy in combination with hormonal therapies in breast cancer patients. In CRPC, where treatment options following progression on ADT are currently restricted to chemotherapy, CT7001 may provide a novel approach to reduce tumour burden and prolong patient survival.