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Updated: Jun 16, 2025
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
AUY922 improves sensitivity to sunitinib in clear cell renal cell carcinoma based on network pharmacology and in
Zixuan Chen1, Xing Jia1, Yuesong Cai2
1Department of Urology, Tongren Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China.
Abstract:
Clear Cell Renal Cell Carcinoma (ccRCC), the most prevalent form of renal cell carcinoma (RCC), poses a significant threat to human health due to its rising morbidity and mortality rates. Sunitinib, a pivotal targeted drug for the treatment of ccRCC, presents a significant challenge due to the high susceptibility of ccRCC to resistance. HSP90 inhibitor AUY922 has demonstrated anti-tumor activity in a range of cancer types. However, its efficacy in combination with sunitinib for ccRCC treatment has not been evaluated. In this study, we employed bioinformatics, network pharmacology, and in vitro assays to verify that AUY922 inhibits cell viability, proliferation, and migration of ccRCC cell lines 786-O and ACHN, with IC50s of 91.86 μM for 786-O and 115.5 μM for ACHN. The effect of AUY922 enhancing the inhibitory effect of sunitinib on ccRCC was further confirmed. The CCK-8 assay demonstrated that the IC50 of sunitinib was reduced from 15.10 μM to 11.91 μM for 786-O and from 17.65 μM to 13.66 μM for ACHN, after the combined application of AUY922. The EdU assay and wound healing assay indicated that AUY922 augmented the inhibitory impact of sunitinib on the proliferation and migration of ccRCC cells. Western blot and RT-PCR analyses demonstrated that AUY922 increased the sensitivity of ccRCC cells to sunitinib by targeting the HIF-1α/VEGFA/VEGFR pathway. Our study represents the first investigation into the role and mechanism of AUY922 in enhancing the sensitivity of ccRCC to sunitinib. In conclusion, the findings indicate the potential for AUY922 to enhance the therapeutic efficacy of sunitinib and overcome sunitinib resistance in ccRCC.
Insights
HSP90 inhibitor AUY922 enhances sunitinib efficacy against clear cell renal cell carcinoma (ccRCC). This combination therapy overcomes sunitinib resistance by targeting the HIF-1α/VEGFA/VEGFR pathway, improving ccRCC treatment outcomes.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Clear Cell Renal Cell Carcinoma (ccRCC) is the most common kidney cancer subtype.
- Sunitinib is a key targeted therapy for ccRCC, but resistance is a major clinical challenge.
- HSP90 inhibitor AUY922 shows anti-tumor potential but its combination with sunitinib for ccRCC is unexplored.
Purpose of the Study:
- To investigate the efficacy of AUY922 in combination with sunitinib for ccRCC treatment.
- To elucidate the underlying molecular mechanisms of AUY922 in overcoming sunitinib resistance.
- To evaluate AUY922's direct anti-tumor effects on ccRCC cell lines.
Main Methods:
- Bioinformatics and network pharmacology approaches.
- In vitro assays including CCK-8, EdU, and wound healing assays.
- Molecular analyses using Western blot and RT-PCR to assess pathway modulation.
Main Results:
- AUY922 demonstrated direct inhibition of ccRCC cell viability, proliferation, and migration.
- Combination therapy significantly reduced sunitinib's IC50 values in ccRCC cells.
- AUY922 potentiated sunitinib's anti-proliferative and anti-migratory effects.
- AUY922 enhanced ccRCC sensitivity to sunitinib by modulating the HIF-1α/VEGFA/VEGFR pathway.
Conclusions:
- AUY922 exhibits anti-tumor activity and can overcome sunitinib resistance in ccRCC.
- The combination of AUY922 and sunitinib presents a promising therapeutic strategy for ccRCC.
- Targeting the HIF-1α/VEGFA/VEGFR pathway is crucial for AUY922's synergistic effect with sunitinib.
