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Mechanisms of resistance to VHL loss-induced genetic and pharmacological vulnerabilities

Jianfeng Ge1,2, Shoko Hirosue1, Leticia Castillon3

  • 1MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK.

EMBO Molecular Medicine
|December 19, 2025
PubMed

Insights

Loss of the von Hippel-Lindau (VHL) tumor suppressor protein creates vulnerabilities in cancer cells. Targeting the HIF1A pathway can eliminate VHL-deficient cells and impact resistance to cancer therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The von Hippel-Lindau (VHL) tumor suppressor is crucial for cellular response to hypoxia and is targeted by VHL-based PROTACs.
  • VHL loss is essential for cell proliferation but acts as a tumor suppressor in renal cell carcinoma.

Purpose of the Study:

  • To investigate the functional consequences of VHL loss in human renal epithelial cells.
  • To identify therapeutic strategies for eliminating VHL-null cells.

Main Methods:

  • Genome-wide CRISPR-Cas9 screening was employed in human renal epithelial cells.
  • Analysis of the HIF1A/ARNT complex's role in VHL-deficient cells.

Main Results:

  • VHL loss leads to HIF1A/ARNT complex-mediated inhibition of cellular fitness and mitochondrial respiration.
  • VHL-null cells exhibit HIF1A-dependent vulnerabilities targetable by pharmacological agents.
  • Combined VHL/HIF1A inactivation confers resistance to VHL-based bromodomain degraders like ARV-771.

Conclusions:

  • The VHL-HIF1A axis presents therapeutic opportunities for targeting VHL-deficient neoplastic clones.
  • Understanding this axis is critical for predicting and overcoming resistance to PROTAC-based cancer therapies.
Keywords:
CRISPR/Cas9 ScreeningHIF1APROTACRenal Cancervon Hippel-Lindau Tumor Suppressor (VHL)

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