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Therapeutic Targeting of Sunitinib-Induced AR Phosphorylation in Renal Cell Carcinoma
Remi Adelaiye-Ogala1,2, Nur P Damayanti1, Ashley R Orillion1,3
1Genitourinary Program, Simon Cancer Center, Indiana University, Indianapolis, Indiana.
Abstract:
Androgen receptor (AR) plays a crucial role in the development and progression of prostate cancer. AR expression has also been reported in other solid tumors, including renal cell carcinoma (RCC), but its biological role here remains unclear. Through integrative analysis of a reverse phase protein array, we discovered increased expression of AR in an RCC patient-derived xenograft model of acquired resistance to the receptor tyrosine kinase inhibitor (RTKi) sunitinib. AR expression was increased in RCC cell lines with either acquired or intrinsic sunitinib resistance in vitro An AR signaling gene array profiler indicated elevated levels of AR target genes in sunitinib-resistant cells. Sunitinib-induced AR transcriptional activity was associated with increased phosphorylation of serine 81 (pS81) on AR. Additionally, AR overexpression resulted in acquired sunitinib resistance and the AR antagonist enzalutamide-induced AR degradation and attenuated AR downstream activity in sunitinib-resistant cells, also indicated by decreased secretion of human kallikrein 2. Enzalutamide-induced AR degradation was rescued by either proteasome inhibition or by knockdown of the AR ubiquitin ligase speckle-type POZ protein (SPOP). In vivo treatment with enzalutamide and sunitinib demonstrated that this combination efficiently induced tumor regression in a RCC model following acquired sunitinib resistance. Overall, our results suggest the potential role of AR as a target for therapeutic interventions, in combination with RTKi, to overcome drug resistance in RCC.Significance: These findings highlight the therapeutic potential of targeting the androgen receptor to overcome RCC resistance to receptor tyrosine kinase inhibitors. Cancer Res; 78(11); 2886-96. ©2018 AACR.
Insights
Targeting androgen receptor (AR) can overcome resistance to sunitinib in renal cell carcinoma (RCC). Combining AR antagonist enzalutamide with sunitinib effectively regressed tumors in a preclinical RCC model.
Area of Science:
- Oncology
- Molecular Biology
- Drug Resistance
Background:
- Androgen receptor (AR) is critical in prostate cancer and its role in renal cell carcinoma (RCC) is unclear.
- Acquired resistance to receptor tyrosine kinase inhibitors (RTKi) like sunitinib is a significant challenge in RCC treatment.
Purpose of the Study:
- To investigate the biological role of AR in acquired resistance to sunitinib in renal cell carcinoma (RCC).
- To evaluate the therapeutic potential of targeting AR in combination with RTKi to overcome drug resistance in RCC.
Main Methods:
- Integrative analysis of patient-derived xenograft models and cell lines to assess AR expression in sunitinib-resistant RCC.
- Utilized AR signaling gene array profiler and Western blotting to analyze AR activity and downstream targets.
- Investigated the effect of AR antagonist enzalutamide on sunitinib-resistant RCC cells and xenograft models, including rescue experiments with proteasome inhibitors and SPOP knockdown.
Main Results:
- Increased AR expression and elevated AR target gene levels were observed in sunitinib-resistant RCC models and cell lines.
- AR overexpression conferred acquired sunitinib resistance, while enzalutamide treatment degraded AR and reduced downstream signaling.
- Combination therapy of enzalutamide and sunitinib demonstrated significant tumor regression in a preclinical model of acquired sunitinib resistance in RCC.
Conclusions:
- Androgen receptor (AR) plays a significant role in acquired resistance to sunitinib in renal cell carcinoma (RCC).
- Targeting AR with enzalutamide, in combination with RTKi sunitinib, represents a promising therapeutic strategy to overcome drug resistance in RCC.
- These findings underscore the potential of AR as a therapeutic target for improving outcomes in RCC patients resistant to RTKi therapy.
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