VHL loss predicts response to Aurora kinase A inhibitor in renal cell carcinoma cells

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Real-Time Monitoring of Aurora kinase A Activation using Conformational FRET Biosensors in Live Cells

Published on: July 30, 2020

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Xiao-Fei Ding1, Jun Zhou2, Guang Chen3

  • 1Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P.R. China.

Molecular Medicine Reports
|May 31, 2018
PubMed

Insights

Von Hippel-Lindau (VHL) tumor suppressor activity influences response to Aurora kinase A (AURKA) inhibitors in renal cell carcinoma (RCC). VHL loss predicts sensitivity to AURKA inhibitors, offering a potential biomarker for treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biomarker Discovery

Background:

  • Identifying specific biomarkers is crucial for improving anticancer agent efficacy, as current molecular targets benefit only a subset of patients.
  • The von Hippel-Lindau (VHL) tumor suppressor's role in therapeutic response to Aurora kinase A (AURKA) inhibitors in renal cell carcinoma (RCC) is under investigation.

Purpose of the Study:

  • To investigate the influence of VHL tumor suppressor activity on the therapeutic response to AURKA inhibitors in human RCC.
  • To determine if VHL expression can serve as a predictive biomarker for AURKA inhibitor efficacy in RCC.

Main Methods:

  • Evaluated VHL protein (pVHL) expression in human RCC cell lines (CAKI, ACHN, 786-O, 769-P, A498) using immunoblotting.
  • Assessed the anti-tumor activity of alisertib (an AURKA inhibitor) in vitro (Cell Counting Kit-8 assay) and in vivo (mouse xenograft model).
  • Investigated VHL-mediated anti-tumor activity by manipulating VHL expression (loss or gain) in 769-P and CAKI cells.

Main Results:

  • VHL-deficient RCC cells (786-O, 769-P, A498) showed sensitivity to alisertib.
  • Conversely, alisertib-resistant RCC cells (CAKI, ACHN) expressed wild-type VHL.
  • VHL knockdown decreased and VHL rescue increased alisertib's anti-proliferation activity in RCC cells.
  • An inverse correlation between VHL gene expression and alisertib sensitivity was confirmed in xenograft models.

Conclusions:

  • VHL loss is associated with sensitivity to AURKA inhibitors in RCC.
  • VHL deficiency may serve as a predictive biomarker for the efficacy of AURKA inhibitors in renal cell carcinoma treatment.

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