Related Experiment Video

Updated: Jul 3, 2026

Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
05:36

Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane

Published on: February 8, 2020

Synthetic essentiality of TRAIL/TNFSF10 in VHL-deficient renal cell carcinoma

Xuechun Wang1, Yujing Qin1, Loan D Duong1,2

  • 1Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556.

Proceedings of the National Academy of Sciences of the United States of America
|July 1, 2026
PubMed

Insights

Clear cell renal cell carcinoma (ccRCC) is driven by VHL loss and HIF2α activation. Targeting tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise for ccRCC combination therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Clear cell renal cell carcinoma (ccRCC) is an aggressive kidney cancer subtype.
  • Loss of the von Hippel-Lindau (VHL) tumor suppressor gene leads to hypoxia-inducible factor-alpha (HIFα) activation, a key driver in ccRCC.
  • The VHL-HIFα axis, particularly HIF2α, is a critical therapeutic target in ccRCC.

Purpose of the Study:

  • To investigate the role and therapeutic potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in VHL-deficient ccRCC.
  • To explore the synthetic essentiality of TRAIL in ccRCC cells.
  • To evaluate combination therapy strategies involving HIF2α inhibition and TRAIL.

Main Methods:

  • Analysis of TRAIL expression in ccRCC tissues and cell lines.
  • Genetic manipulation (depletion) of TRAIL and HIF2α.
  • Pharmacological inhibition of HIF2α using belzutifan.
  • Cell proliferation assays and cell cycle analysis.
  • Assessment of ccRCC cell and tumor models.

Main Results:

  • TRAIL is upregulated in ccRCC in a VHL-HIF2α-dependent manner.
  • TRAIL is selectively essential for ccRCC cell proliferation, promoting cell cycle progression via the p38 MAPK pathway.
  • Depleting TRAIL or inhibiting HIF2α with belzutifan sensitizes ccRCC cells to recombinant TRAIL.
  • Combination of TRAIL and belzutifan demonstrates therapeutic potential in ccRCC models.

Conclusions:

  • TRAIL is a VHL-HIF2α-regulated, essential gene in ccRCC.
  • Targeting TRAIL, especially in combination with HIF2α inhibition, represents a promising therapeutic strategy for ccRCC.
  • The VHL-HIF2α-TRAIL axis offers novel opportunities for ccRCC treatment.
Keywords:
HIF2αTRAILVHLbelzutifanrenal cell carcinoma

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