Mechanisms of resistance to VHL loss-induced genetic and pharmacological vulnerabilities
The von Hippel-Lindau tumor suppressor (VHL) is a component of a ubiquitin ligase complex that controls cellular responses to hypoxia. Endogenous VHL is also utilized by proteolysis-targeting chimera (PROTAC) protein degraders, a promising class of anti-cancer agents. VHL is broadly essential for cell proliferation, yet it is a key tumor suppressor in renal cell carcinoma. To understand the functional consequences of VHL loss, and to identify targeted approaches for the elimination of VHL null cells, we have used genome-wide CRISPR-Cas9 screening in human renal epithelial cells. We find that, upon VHL loss, the HIF1A/ARNT complex is the central inhibitor of cellular fitness, suppressing mitochondrial respiration, and that VHL null cells show HIF1A-dependent molecular vulnerabilities that can be targeted pharmacologically. Combined VHL/HIF1A inactivation in breast and esophageal cancer cells can also provide resistance to ARV-771, a VHL-based bromodomain degrader that has anti-cancer activity. HIF1A stabilization can thus provide opportunities for early intervention in neoplastic VHL clones, and the VHL-HIF1A axis may be relevant for the development of resistance to the emerging class of PROTAC-based cancer therapies.
Authors
- Shoko Hirosue (ORCID: https://orcid.org/0000-0003-1287-471X)
- Leticia Castillon (ORCID: https://orcid.org/0009-0007-2110-3825)
- Saroor A. Patel (ORCID: https://orcid.org/0000-0002-6331-1557)
- Daniel Muñoz‐Espín (ORCID: https://orcid.org/0000-0002-0550-9514)
- Jarno Drost (ORCID: https://orcid.org/0000-0002-2941-6179)
- Cissy Yong (ORCID: https://orcid.org/0000-0002-8697-1494)
- Jianfeng Ge (ORCID: https://orcid.org/0000-0003-0972-3312)
- Ludovic Wesolowski
- Sakari Vanharanta (ORCID: https://orcid.org/0000-0001-5619-7963)
- Anna C. Obenauf (ORCID: https://orcid.org/0000-0002-9556-5914)
- Grant Duncan Stewart (ORCID: https://orcid.org/0000-0003-3188-9140)
- Anna Dyas
- Sanne de Haan
Institutions
- University of Helsinki (FI)
- Utrecht University (NL)
- Research Institute of Molecular Pathology (AT)
- University of Cambridge (GB)
- Cancer Research UK (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Wellcome Sanger Institute (GB)
- Cancer Research UK Cambridge Center (GB)
- MRC Cancer Unit (GB)
- Hutchison/MRC Research Centre (GB)
- Princess Máxima Center (NL)
- Vienna Biocenter (AT)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-12-19
- DOI
- https://doi.org/10.1038/s44321-025-00361-w
- Citations
- 1
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Cancer Research UK
- National Institute for Health and Care Research
- Department of Health and Social Care
- Kidney Research UK
- European Commission
- Rosetrees Trust
- Sigrid Juséliuksen Säätiö
- Syöpäsäätiö
- Medical Research Council
- NIHR Cambridge Biomedical Research Centre