Abstract The clinical treatment of castration-resistant prostate cancer (CRPC) is currently a major challenge. This study explored a new combination strategy for CRPC that targeted androgen receptor (AR)-dependent and AR-independent mechanisms. First, the degradation efficiency of AR by ARV-110 was verified. CCK-8 and CellTiter-Glo assays were used to evaluate the viability of CRPC cells after treatment. The combination index of platelet-derived growth factor receptor (PDGFR) inhibitors combined with ARV-110 was calculated using CompuSyn software. Transcriptome sequencing was used to explore the in-depth mechanisms of the combination strategy. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to clarify the transcriptional regulatory relationships. Coimmunoprecipitation was used to evaluate protein interactions. The results showed that ARV-110 significantly promoted AR degradation. The combination of ARV-110 and ponatinib exerted a significant inhibitory and synergistic effect on CRPC cells. The effective targets were AR and PDGFR. The combination of ARV-110 and the PDGFR-selective inhibitor JNJ10198409 effectively induced the apoptosis of CRPC cells. ARV-110 alone promoted the transcription of PDGFA. And the combination strategy further induced JNK signaling pathway activation and promoted cell apoptosis by inhibiting PDGFR activity. Additionally, the substantial accumulation of reactive oxygen species induced by the combination strategy was related to the joint downregulation of catalase by the two drugs through different mechanisms. In conclusion, this study described a new strategy for the treatment of CRPC and clarified the molecular mechanisms of the combination strategy, providing a new theoretical basis for the precision treatment of CRPC.
Fu et al. (Fri,) studied this question.