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Cellular and Molecular Biology

The novel CDK9 inhibitor, XPW1, alone and in combination with BRD4 inhibitor JQ1, for the treatment of clear cell renal cell carcinoma

British Journal of Cancer volume 129, pages 1915–1929 (2023)Cite this article

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Abstract

Background

Clear cell renal cell carcinoma (ccRCC) is a highly lethal malignancy with few therapeutic options. Cyclin‑dependent kinase 9 (CDK9), a potential therapeutic target of many cancers, has been recently observed to be upregulated in ccRCC patients. Therefore, we aimed to investigate the therapeutic potential of CDK9 in ccRCC and develop a novel CDK9 inhibitor with low toxicity for ccRCC treatment.

Methods

The expression of CDK9 in ccRCC was checked using the online database and tissue microarray analysis. shRNA-mediated CDK9 knockdown and CDK inhibitor were applied to evaluate the effect of CDK9 on ccRCC. Medicinal chemistry methods were used to develop a new CDK9 inhibitor with drugability. RNA-seq and ChIP-seq experiments were conducted to explore the mechanism of action. MTS, western blotting, and colony formation assays were performed to evaluate the anti-ccRCC effects of CDK9 knockdown and inhibition in vitro. The in vivo anti-tumour efficacy was evaluated in a xenograft model.

Results

CDK9 is overexpressed and associated with poor survival in ccRCC. Knockdown or inhibition of CDK9 significantly suppressed ccRCC cells. XPW1 was identified as a new potent and selective CDK9 inhibitor with excellent anti-ccRCC activity and low toxicity. In mechanism, XPW1 transcriptionally inhibited DNA repair programmes in ccRCC cells, resulting in an excellent anti-tumour effect. CDK9 and BRD4 were two highly correlated transcriptional regulators in ccRCC patients, and the BRD4 inhibitor JQ1 enhanced XPW1’s anti-ccRCC effects in vitro and in vivo.

Conclusions

This work provides valuable insights into the therapeutic potential of CDK9 in ccRCC. The CDK9 inhibitor XPW1 would be a novel therapeutic agent for targeting ccRCC, alone or in rational combinations.

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Fig. 1: CDK9 is upregulated and associated with poor survival in ccRCC.
Fig. 2: The shRNA-mediated CDK9 knockdown and CDK9 inhibitor suppressed cell proliferation, colony formation, and tumour growth in ccRCC.
Fig. 3: Development of novel potential CDK9 inhibitors.
Fig. 4: Anti-ccRCC effect of XPW1 and iCDK9 in vivo.
Fig. 5: XPW1 preferentially suppresses gene expression in terms of transcriptional manner.
Fig. 6: Identification of BRD4 inhibitor JQ1 as a potential enhancer for combination therapy with XPW1 in ccRCC cells.
Fig. 7: Efficacy of combined XPW1 and JQ1 treatment in vivo.

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Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

The authors thank all staffs who assisted with the study.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82125028 and 82102746) and the Fundamental Research Funds for the Central Universities of China (No. 20720180051).

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Author notes

  1. These authors contributed equally: Zhijian Kuang, Kaiqiang Guo, Yin Cao, Mengxue Jiang.

Authors and Affiliations

  1. Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, 361102, Xiamen, China

    Zhijian Kuang, Kaiqiang Guo, Yin Cao, Chaojie Wang, Qiaoqiong Wu, Guosheng Hu, Mingtao Ao, Mingfeng Huang, Jingbo Qin, Taige Zhao, Sheng Lu, Cuiling Sun, Mingyu Li, Tong Wu, Wen Liu & Meijuan Fang

  2. College of Arts, Sichuan University, 610207, Chengdu, China

    Kaiqiang Guo

  3. School of Medicine, Xiamen University, 361102, Xiamen, China

    Mengxue Jiang

  4. Jiangxi Cancer Hospital (The Second Affiliated Hospital of Nanchang Medical Colloge), 519 East Beijing Rd, 330029, Nanchang, Jiangxi, China

    Chaojie Wang

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  1. Zhijian Kuang
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Contributions

Study design: ZK, KG, TW, WL and MF; data collection: ZK, KG, YC, MJ, CW, QW, TZ and SL; bioinformatics and statistics: GH and TW; methodology: ZK, KG, MA and JQ; data analysis: ZK, KG, YC, MJ and MH; technical support: CS and ML; study supervision: WL and MF; writing—original draft: ZK, KG, YC and MJ; writing—review and editing: TW, WL and MF.

Corresponding authors

Correspondence to Tong Wu, Wen Liu or Meijuan Fang.

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The animal studies were approved by the Ethics Committee for Animal Experimentation and Animal Welfare at Xiamen University. The study involved no human subjects.

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Kuang, Z., Guo, K., Cao, Y. et al. The novel CDK9 inhibitor, XPW1, alone and in combination with BRD4 inhibitor JQ1, for the treatment of clear cell renal cell carcinoma. Br J Cancer 129, 1915–1929 (2023). https://doi.org/10.1038/s41416-023-02464-y

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