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Updated: Jun 13, 2025
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Synthetic essentiality of TRAIL/TNFSF10 in VHL-deficient renal cell carcinoma
Xuechun Wang1, Loan Duong1,2, Yujing Qin1
1Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA.
Abstract:
Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of kidney cancer. Loss of von Hippel-Lindau (VHL) and the consequent activation of hypoxia-inducible factor-α (HIFα, especially HIF2α) plays an essential role in ccRCC initiation and progression. The approved HIF2α inhibitor belzutifan faces the challenge of resistance, presenting an opportunity of co-targeting HIF2α and another vulnerability. This study elucidates the synthetic essentiality of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) in VHL-deficient ccRCC, uncovering a novel reciprocal regulation between HIF2α and TRAIL. TRAIL was identified as a direct transcriptional target of HIF2α and paradoxically found to be crucial for cell proliferation, primarily by activating the p38 MAPK pathway and facilitating G1/S phase transition. Depletion of endogenous TRAIL or inhibition of HIF2α with belzutifan sensitizes ccRCC cells to recombinant TRAIL, presenting a promising avenue for combination therapy to overcome both TRAIL resistance and belzutifan resistance in treating ccRCC.
Insights
Clear cell renal cell carcinoma (ccRCC) involves VHL loss and HIF2α activation. Targeting HIF2α and TRAIL offers a new combination therapy to overcome resistance in ccRCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Clear cell renal cell carcinoma (ccRCC) is an aggressive kidney cancer subtype.
- VHL gene loss activates hypoxia-inducible factor-alpha (HIFα), driving ccRCC.
- Belzutifan, a HIF2α inhibitor, faces resistance challenges.
Purpose of the Study:
- To investigate the role of TRAIL in VHL-deficient ccRCC.
- To uncover the relationship between HIF2α and TRAIL.
- To explore combination therapy for belzutifan-resistant ccRCC.
Main Methods:
- Investigated TRAIL's synthetic essentiality in VHL-deficient ccRCC models.
- Analyzed the regulatory link between HIF2α and TRAIL.
- Assessed the impact of TRAIL depletion or HIF2α inhibition on ccRCC cell sensitivity to recombinant TRAIL.
Main Results:
- TRAIL is a direct transcriptional target of HIF2α in ccRCC.
- TRAIL promotes ccRCC cell proliferation via p38 MAPK and G1/S transition.
- HIF2α inhibition or TRAIL depletion sensitizes ccRCC cells to recombinant TRAIL.
Conclusions:
- TRAIL plays a critical, paradoxical role in ccRCC proliferation.
- A novel reciprocal regulation exists between HIF2α and TRAIL.
- Combination therapy targeting HIF2α and TRAIL may overcome resistance in ccRCC.
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