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.

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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
The authors are grateful to the Institute of Urology and Department of Urology, First Hospital of China Medical University, for their general support. The completion of graphical abstract is supported by Figdraw (ID:YWUUAacbbc).
Funding
This study was funded by the 2024 Shenyang Science and Technology Plan – Public Health R&D Special Project (Key Technologies for Diagnosis and Treatment of Major Diseases, No.24-214-3-06), Liaoning Provincial Science and Technology Joint Program (Key Technology Breakthrough Project, No. 2024JH2/102600311) and National Nature Science Foundation of China (Grant No. 82172568).
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The author contributions according to CRediT classification are as follows: YF and CYP conceived the study and designed the experiments. YF and JBB contributed to methodology. YF, HYZ, and SSS performed experiments and analyzed data. JBB, YTW, and GXL investigated the study. YF, DQZ, and SSS performed formal analysis. JBB performed funding acquisition. JBB and CYP supervised the study. YF and SSS contributed to writing—original draft preparation. CYP and JBB contributed to writing—review, and editing. All authors read and approved the final manuscript.
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This study was conducted in accordance with ethical standards and national and international guidelines. All animal experiments were carried out according to the protocol approved by the China Medical University Guidelines for Use and Care of Animals (ethical approval code number: 2022246). This study was approved by the Medical Ethics Committee of the First Hospital of China Medical University. (ethical approval code number: AF-SOP-07-1.1-01), and all patients provided written informed consent.
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Fu, Y., Sun, S., Liu, G. et al. Mechanism and therapeutic significance of ARV-110 combined with a PDGFR inhibitor for the induction of apoptosis in castration-resistant prostate cancer cells through the ROS/JNK pathway. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08718-w
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DOI: https://doi.org/10.1038/s41419-026-08718-w


