The CDK4/6 inhibitor dalpiciclib augments the antitumor efficacy of enzalutamide in preclinical models of castration-resistant prostate cancer through inhibition of MCM4-mediated DNA replication

Castration-resistant prostate cancer (CRPC) is a lethal malignancy characterized by frequent alterations in cell cycle regulatory pathways, particularly the Cyclin/CDK/RB axis. Several clinical trials are currently evaluating CDK4/6 inhibitors in prostate cancer; however, clinical evidence remains limited.Although the androgen receptor (AR) inhibitor enzalutamide (ENZ) initially shows therapeutic efficacy, patients eventually develop resistance, and monotherapy provides limited antitumor benefit. In this study, we performed pharmacological profiling, genomic dependency analysis, RNA sequencing, and functional validation across multiple in vitro and in vivo preclinical CRPC models. The combination of ENZ and the CDK4/6 inhibitor dalpiciclib (DAL) exhibited potent antitumor activity in CRPC cell lines and a cell-derived xenograft (CDX) model. Furthermore, ENZ combined with DAL suppressed cell cycle progression, migration, and DNA replication while promoting apoptosis in CRPC cells. Mechanistically, ENZ inhibited AR-mediated transcriptional activation of MCM4, a key DNA helicase component, thereby enhancing the inhibitory effect of CDK4/6 blockade on DNA replication and resulting in a marked synergistic antitumor response. Collectively, these findings propose the ENZ-DAL combination as a promising therapeutic strategy to improve treatment efficacy and support further clinical evaluation of this regimen in patients with CRPC.