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DR5/WDR12 balances p65 stability promoting sunitinib resistance in renal cell carcinoma

Cell Death & Differentiation (2026)Cite this article

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Abstract

Although the use of tyrosine kinase inhibitors (TKIs), such as sunitinib, has led to impressive advancements in the treatment of clear cell renal cell carcinoma (ccRCC), primary or acquired resistance to sunitinib remains elusive. Here, we report that death receptor 5 (DR5) is upregulated in ccRCC tissues and sunitinib-resistant cells, and is associated with poor outcomes and sunitinib resistance. Gain- and loss-of-function experiments revealed that DR5 promotes sunitinib resistance both in vitro and in vivo. Mechanistically, DR5 enhances the activation of NF-κB signalling by reducing the ubiquitin-mediated proteasomal degradation of p65 via competitive binding to the CUL4B-DDB1 E3 ligase complex linker protein WDR12, leading to the transcriptional upregulation of DR5 and BCL2. The positive feedback loop between DR5 and p65 contributes to the upregulation of BCL2 expression, which in turn modulates sunitinib resistance in ccRCC. Notably, targeting the DR5/NF-κB/BCL2 axis sensitizes ccRCC cells to sunitinib both in vitro and in vivo. Clinically, ccRCC patients with high DR5 expression show decreased responsiveness to TKI-based therapy. Collectively, these results highlight the importance of the positive feedback loop involving the DR5/NF-κB axis in sunitinib resistance and provide an effective therapeutic strategy for overcoming resistance.

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Fig. 1: DR5 is upregulated and is associated with poor prognosis in RCC.
Fig. 2: DR5 regulates the sensitivity of ccRCC cells to sunitinib in vitro and in vivo.
Fig. 3: DR5 activates the NF-κB pathways in ccRCC.
Fig. 4: The positive feedback loop of DR5-p65 promotes sunitinib resistance through mediating the transcription of BCL-2.
Fig. 5: DR5 stabilizes p65 protein in renal cancer by competitively binding to WDR12.
Fig. 6: WDR12 is responsible for DR5-induced sunitinib resistance in ccRCC.
Fig. 7: Withaferin A treatment overcomes DR5-mediated sunitinib resistance in ccRCC.
Fig. 8: High DR5 expression correlates with poor therapeutic responses to TKIs-based therapy in ccRCC patients.

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Data availability

The data analyzed in this study were obtained from the Gene Expression Omnibus (GEO) databases at GSE54052 and GSE68629. The sequence data generated in this study have been deposited in the NCBI SRA database (SRA PRJNA1236818).

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Acknowledgements

We sincerely thank Prof. Xiaoping Zhang for providing the sunitinib-resistant RCC cells. We thank all the patients involved in this study.

Funding

This work was supported by grants from the Minimally Invasive Innovation Team of the Urology Department of the Chinese PLA General Hospital (X. Zhang), the Priority Specialty in Medicine (X. Zhang), Development of Key Clinical Specialties (X. Zhang), the Pioneer Program for Discipline Innovation and Development of the Third Medical Center of PLA General Hospital (2024BJ-11 to Y. Huang), the Youth Fund of Chinese PLA General Hospital (22QNCZ022 to Y. Huang), National Natural Science Foundation of China (82373233 to T. Shi) and Key Research and Development Project of Hainan Provincial Science and Technology Department (ZDYF2021SHFZ056 to T. Shi).

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  1. These authors contributed equally: Wen Tao, Yuhao Dong, Shidong Zuo, Hanfeng Wang.

Authors and Affiliations

  1. Department of Urology, The Third Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China

    Wen Tao, Yuhao Dong, Shidong Zuo, Hanfeng Wang, Qiyang Liang, Tianwei Cai, Xinran Chen, Wenjie Wei, Chi Zhang, Shuo Tian, Chuang Wang, Hongzhao Li, Baojun Wang, Xin Ma, Qingbo Huang, Yan Huang & Xu Zhang

  2. Department of Urology Laboratory, Chinese PLA General Hospital, Beijing, China

    Wen Tao, Yuhao Dong, Shidong Zuo, Hanfeng Wang, Qiyang Liang, Tianwei Cai, Xinran Chen, Wenjie Wei, Chi Zhang, Shuo Tian, Chuang Wang, Hongzhao Li, Baojun Wang, Xin Ma, Qingbo Huang, Yan Huang & Xu Zhang

  3. Medical School of PLA, Beijing, China

    Wen Tao, Yuhao Dong, Shidong Zuo, Qiyang Liang, Tianwei Cai, Xinran Chen, Wenjie Wei, Chi Zhang, Shuo Tian & Chuang Wang

  4. Department of Urology, Hainan Hospital of the Chinese PLA General Hospital, Beijing, China

    Taoping Shi

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Contributions

W. Tao: Conceptualization, data curation, formal analysis, visualization, investigation, methodology, writing-original draft, writing-review and editing. Y. Dong: Data curation, investigation, and methodology. S. Zuo: Formal analysis, investigation, methodology. H. Wang: Investigation and methodology. Q. Liang: Formal analysis and investigation. T. Cai: Formal analysis and investigation. X. Chen: Investigation. W. Wei: Formal analysis. C. Zhang: Investigation. S. Tian: Investigation. C. Wang: Formal analysis. H. Li: Data curation and resources. B. Wang: Data curation and resources. X. Ma: Conceptualization, data curation, resources. Q. Huang: Conceptualization, data curation, resources. T. Shi: Conceptualization, data curation, funding acquisition. Y. Huang: Conceptualization, data curation, formal analysis, investigation, funding acquisition, resources, supervision, project administration, writing-review and editing. X. Zhang: Conceptualization, data curation, formal analysis, investigation, funding acquisition, resources, supervision, project administration and writing-review.

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Correspondence to Taoping Shi, Yan Huang or Xu Zhang.

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Ethical approval for the animal experiments was obtained from the Ethics Committee of the Chinese People’s Liberation Army (PLA) General Hospital. The collection of human tissues was approved by the Ethics and Research Committee of the Chinese PLA General Hospital and written informed consent was obtained from the patients before surgery.

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Tao, W., Dong, Y., Zuo, S. et al. DR5/WDR12 balances p65 stability promoting sunitinib resistance in renal cell carcinoma. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01723-8

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