2. Academic Validation
  3. DR5/WDR12 balances p65 stability promoting sunitinib resistance in renal cell carcinoma

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

  • Cell Death Differ. 2026 Mar 23. doi: 10.1038/s41418-026-01723-8.
Wen Tao # 1 2 3,  Yuhao Dong # 1 2 3,  Shidong Zuo # 1 2 3,  Hanfeng Wang # 1 2,  Qiyang Liang 1 2 3,  Tianwei Cai 1 2 3,  Xinran Chen 1 2 3,  Wenjie Wei 1 2 3,  Chi Zhang 1 2 3,  Shuo Tian 1 2 3,  Chuang Wang 1 2 3,  Hongzhao Li 1 2,  Baojun Wang 1 2,  Xin Ma 1 2,  Qingbo Huang 1 2,  Taoping Shi 4,  Yan Huang 5 6,  Xu Zhang 7 8
Affiliations

Affiliations

  • 1 Department of Urology, The Third Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.
  • 2 Department of Urology Laboratory, Chinese PLA General Hospital, Beijing, China.
  • 3 Medical School of PLA, Beijing, China.
  • 4 Department of Urology, Hainan Hospital of the Chinese PLA General Hospital, Beijing, China. [email protected].
  • 5 Department of Urology, The Third Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China. [email protected].
  • 6 Department of Urology Laboratory, Chinese PLA General Hospital, Beijing, China. [email protected].
  • 7 Department of Urology, The Third Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China. [email protected].
  • 8 Department of Urology Laboratory, Chinese PLA General Hospital, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 41872532 DOI: 10.1038/s41418-026-01723-8
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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