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DHODH inhibition represents a therapeutic strategy and improves abiraterone treatment in castration-resistant prostate cancer

Oncogene (2024)Cite this article

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Abstract

Castration-resistant prostate cancer (CRPC) is an aggressive disease with poor prognosis, and there is an urgent need for more effective therapeutic targets to address this challenge. Here, we showed that dihydroorotate dehydrogenase (DHODH), an enzyme crucial in the pyrimidine biosynthesis pathway, is a promising therapeutic target for CRPC. The transcript levels of DHODH were significantly elevated in prostate tumors and were negatively correlated with the prognosis of patients with prostate cancer. DHODH inhibition effectively suppressed CRPC progression by blocking cell cycle progression and inducing apoptosis. Notably, treatment with DHODH inhibitor BAY2402234 activated androgen biosynthesis signaling in CRPC cells. However, the combination treatment with BAY2402234 and abiraterone decreased intratumoral testosterone levels and induced apoptosis, which inhibited the growth of CWR22Rv1 xenograft tumors and patient-derived xenograft organoids. Taken together, these results establish DHODH as a key player in CRPC and as a potential therapeutic target for advanced prostate cancer.

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Fig. 1: DHODH overexpression associates with CRPC and is a critical dependency of CRPC cell survival and proliferation.
Fig. 2: DHODH inhibitor inhibits proliferation and survival in CRPC cells.
Fig. 3: DHODH inhibition induces DNA damage, blocks the cell cycle and DNA replication in CRPC cells.
Fig. 4: DHODH inhibitor exerts potent antitumor activity in CRPC in vitro and in vivo.
Fig. 5: DHODH inhibition activates intracrine androgen biosynthesis pathway.
Fig. 6: Combine DHODH inhibitor and abiraterone treatment adds sensitivity of CRPC inhibition and blocks intracrine androgen.

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Data availability

Data files and specific code used to perform all analyses in this manuscript are available at https://github.com/Wangjunjian-lab/DHODH-inhibition-improves-abiraterone-treatment-in-CRPC/tree/main.

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Acknowledgements

We thank the Laboratory Animal Center of Sun Yat-sen University for providing the technologies equipment.

Funding

This research was supported by the National Natural Science Foundation of China (82273956), the Guangdong Basic and Applied Basic Research Foundation (2022B1515130008), the Key Research and Development Plan of Guangzhou City (202206080007), and Science and Technology Planning Project of Guangdong Province (2023A0505010013).

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Authors and Affiliations

  1. School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou, Guangdong, China

    Shaoqiang Guo, Miaomiao Miao, Yufeng Wu, Qinyan Wu, Guoping Zhong & Junjian Wang

  2. The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China

    Dongyue Pan

  3. Guangdong Engineering Research Center of Urinary Continence and Reproductive Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, Guangdong, China

    Zhanfang Kang & Jianwen Zeng

  4. Department of Urologic Surgery, University of California, Davis, CA, USA

    Chengfei Liu

  5. UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, USA

    Chengfei Liu

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Contributions

JJW, CFL, and GPZ conceived of and designed the experiments. SQG, MMM, YFW, and QYW performed the experiments and collected data. DYP and ZFK performed the bioinformatics analysis. SQG, JWZ, JJW, and CFL wrote and edited the manuscript. All authors agree with the published version of the manuscript.

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Correspondence to Guoping Zhong, Chengfei Liu or Junjian Wang.

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Guo, S., Miao, M., Wu, Y. et al. DHODH inhibition represents a therapeutic strategy and improves abiraterone treatment in castration-resistant prostate cancer. Oncogene (2024). https://doi.org/10.1038/s41388-024-03005-4

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