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Updated: May 7, 2026
Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
Molecular Glue cc-885 Inhibits VHL-Deficient Clear Cell Renal Cell Carcinoma via ETS1 Degradation
Taowei Yang1, Qihao Li1, Kun Ye1
1Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Abstract:
Clear cell renal cell carcinoma (ccRCC) is a common and aggressive form of kidney cancer with VHL mutations present in > 50% of cases. These mutations lead to dysregulation of hypoxia-inducible factors (HIFs) and activation of oncogenic pathways, making VHL-deficient ccRCC a challenging target for therapy. In this study, we identified cc-885, a molecular glue degrader, as a selective inhibitor of VHL-deficient ccRCC. cc-885 promotes ubiquitination and degradation of transcription factor ETS1, which cooperates with EPAS1 (HIF-2α) to drive tumorigenesis. We demonstrated that cc-885 selectively targeted the p51 and p42 isoforms of ETS1, disrupting p27/p51 balance and suppressing ETS1 transcriptional activity. Moreover, combining cc-885 with an EPAS1 inhibitor, belzutifan, significantly enhanced the anti-tumor efficacy. Our findings provide a novel and precise therapeutic strategy for VHL-deficient ccRCC by targeting ETS1 degradation and disrupting the ETS1-EPAS1 complex.
Insights
A new drug, cc-885, targets ETS1 degradation to treat VHL-deficient clear cell renal cell carcinoma (ccRCC). Combining cc-885 with belzutifan enhances anti-tumor effects in this aggressive kidney cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Clear cell renal cell carcinoma (ccRCC) is an aggressive kidney cancer often driven by VHL mutations.
- VHL mutations disrupt hypoxia-inducible factors (HIFs), activating oncogenic pathways and posing therapeutic challenges.
Purpose of the Study:
- To identify novel therapeutic strategies for VHL-deficient ccRCC.
- To investigate the potential of cc-885, a molecular glue degrader, as a selective inhibitor.
Main Methods:
- Identified cc-885 as a selective inhibitor of VHL-deficient ccRCC.
- Demonstrated cc-885 promotes ubiquitination and degradation of transcription factor ETS1.
- Investigated the interaction between ETS1 and EPAS1 (HIF-2α).
- Assessed the efficacy of cc-885 alone and in combination with belzutifan (an EPAS1 inhibitor).
Main Results:
- cc-885 selectively targets ETS1 isoforms (p51 and p42), disrupting p27/p51 balance and suppressing ETS1 activity.
- cc-885 promotes ETS1 degradation, a key factor cooperating with EPAS1 in tumorigenesis.
- Combination therapy with cc-885 and belzutifan significantly enhanced anti-tumor efficacy.
Conclusions:
- cc-885 offers a novel therapeutic strategy for VHL-deficient ccRCC by targeting ETS1 degradation.
- Disrupting the ETS1-EPAS1 complex presents a precise approach for treating this challenging cancer.
- Combination therapy shows enhanced efficacy, suggesting a promising clinical application.
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