Related Experiment Video

Updated: Jun 23, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

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CDK4/6 inhibitors dephosphorylate RNF26 to stabilize TSC1 and increase the sensitivity of ccRCC to mTOR inhibitors

Xinlin Liu1,2,3, Wei Li1,2,3, Lu Yi1,2,3

  • 1Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.

British Journal of Cancer
|June 18, 2024
PubMed
Abstract

Insights

A new CDK4/RNF26/TSC1 pathway was discovered in kidney cancer. This axis influences how CDK4/6 and mTOR inhibitors work, offering new therapeutic strategies for clear cell renal cell carcinoma (ccRCC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Combined CDK4/6 and mTOR inhibitors show clinical promise in clear cell renal cell carcinoma (ccRCC).
  • Understanding CDK4/6 pathway mechanisms and drug interactions is crucial for developing novel ccRCC therapies.
  • CDK4/6 inhibitors increase TSC1 protein levels, impacting the mTOR pathway, but the precise regulatory mechanism remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which CDK4/6 inhibitors regulate TSC1.
  • To investigate the role of the CDK4/RNF26/TSC1 axis in ccRCC progression and response to therapy.
  • To identify new therapeutic targets for ccRCC treatment.

Main Methods:

  • Utilized mass spectrometry, coimmunoprecipitation, GST pull-down, immunofluorescence, Western blot, and RT-qPCR to analyze CDK4, RNF26, and TSC1 interactions.
  • Employed Transwell, tube formation, CCK-8, colony formation, and xenograft assays to assess RNF26's biological function in renal cancer.
  • Analyzed TCGA-KIRC dataset and RT-qPCR to examine pathways affected by RNF26 silencing.

Main Results:

  • CDK4/6 inhibitors were found to stabilize TSC1 in cancer cells.
  • CDK4 enhances TSC1-RNF26 interaction; RNF26 activates mTOR signaling, promoting ccRCC progression, angiogenesis, and tumorigenesis.
  • RNF26 acts as an E3 ligase for TSC1, regulating CDK4-induced TSC1 stabilization and negatively impacting ccRCC progression and angiogenesis.

Conclusions:

  • Identified a novel CDK4/RNF26/TSC1 axis regulating ccRCC.
  • This axis is critical for the anticancer efficacy of combined CDK4/6 and mTOR inhibitors in ccRCC.
  • The findings provide a basis for new therapeutic strategies targeting this pathway in ccRCC.

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