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DR5/WDR12 balances p65 stability promoting sunitinib resistance in renal cell carcinoma
Wen Tao1,2,3, Yuhao Dong1,2,3, Shidong Zuo1,2,3
1Department of Urology, The Third Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.
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.
Insights
Death receptor 5 (DR5) drives resistance to sunitinib in clear cell renal cell carcinoma (ccRCC) by activating NF-κB signaling. Targeting this DR5/NF-κB/BCL2 axis can overcome sunitinib resistance in ccRCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Clear cell renal cell carcinoma (ccRCC) treatment has advanced with tyrosine kinase inhibitors (TKIs) like sunitinib.
- However, primary or acquired resistance to sunitinib remains a significant clinical challenge.
Purpose of the Study:
- To investigate the role of death receptor 5 (DR5) in mediating sunitinib resistance in ccRCC.
- To elucidate the underlying molecular mechanisms of DR5-induced resistance.
- To evaluate the therapeutic potential of targeting the DR5 pathway to overcome sunitinib resistance.
Main Methods:
- Analysis of DR5 expression in ccRCC tissues and sunitinib-resistant cells.
- Gain- and loss-of-function experiments to assess DR5's impact on sunitinib resistance in vitro and in vivo.
- Investigation of the molecular mechanism involving NF-κB signaling, p65 degradation, and BCL2 expression.
- Assessment of therapeutic strategies targeting the DR5/NF-κB/BCL2 axis.
Main Results:
- DR5 is upregulated in ccRCC and associated with poor outcomes and sunitinib resistance.
- DR5 promotes sunitinib resistance by enhancing NF-κB activation through a positive feedback loop involving p65 and WDR12.
- This loop leads to increased BCL2 expression, contributing to resistance.
- Targeting the DR5/NF-κB/BCL2 axis sensitized ccRCC cells to sunitinib.
- High DR5 expression correlated with decreased responsiveness to TKI therapy in patients.
Conclusions:
- A positive feedback loop between DR5 and NF-κB signaling is crucial for sunitinib resistance in ccRCC.
- DR5 upregulation, via NF-κB activation and subsequent BCL2 expression, drives resistance.
- Targeting the DR5/NF-κB/BCL2 axis represents a promising therapeutic strategy to overcome sunitinib resistance in ccRCC.
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