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

Jianfeng Ge; Shoko Hirosue; Leticia Castillon; Saroor A. Patel; Ludovic Wesolowski; Anna Dyas; Cissy Yong; Sanne De Haan; Jarno Drost; Grant D. Stewart; Anna C. Obenauf; Daniel Munoz-Espin; Sakari Vanharanta

doi:10.1038/s44321-025-00361-w

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

Jianfeng Ge
, Shoko Hirosue
, Leticia Castillon
, Saroor A. Patel
, Ludovic Wesolowski
, Anna Dyas
, Cissy Yong
, Sanne De Haan
, Jarno Drost
, Grant D. Stewart
, Anna C. Obenauf
, Daniel Munoz-Espin
, Sakari Vanharanta

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Number of pages	21
Journal	EMBO Molecular Medicine
DOIs	https://doi.org/10.1038/s44321-025-00361-w
Publication status	E-pub ahead of print - 19 Dec 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

Funding

We thank M Linehan for the UOK101 cells. GDS is supported by the Mark Foundation for Cancer Research and the Cancer Research UK Cambridge Centre (C9685/A25177). GDS and the Human Research Tissue Bank were supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. SH received a PhD studentship from the Rosetrees Trust. This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sk & lstrok;odowska-Curie grant agreement No 955951. This work was supported by the Medical Research Council (MC_UU_12022/7), Kidney Research UK (RP_033_20170303), the Sigrid Juselius Foundation, the Academy of Finland (decision 338420) and the Cancer Foundation Finland. Munoz-Espin laboratory is supported by a CRUK Programme Foundation Award (C62187/A29760). JG is funded by a Darley/Sands Downing College Fellowship (G109261).

Funders	Funder number
Kidney Research UK	RP_033_20170303
European Commission (EC)	955951
UKRI \| Medical Research Council (MRC)	MC_UU_12022/7
Research Council of Finland (AKA)	338420
Sigrid Jusliuksen Sti (Sigrid Juslius Stiftelse)
NIHR \| NIHR Cambridge Biomedical Research Centre (NIHR Cambridge BRC)	BRC-1215-20014
Darley/Sands Downing College Fellowship
Cancer Foundation Finland
Rosetrees Trust (Rosetrees)
Cancer Research UK (CRUK)	C9685/A25177, C62187/A29760

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

CRISPR/Cas9 Screening
HIF1A
PROTAC
Renal Cancer
von Hippel-Lindau Tumor Suppressor (VHL)

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Cite this

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title = "Mechanisms of resistance to VHL loss-induced genetic and pharmacological vulnerabilities",

abstract = "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.",

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author = "Jianfeng Ge and Shoko Hirosue and Leticia Castillon and Patel, \{Saroor A.\} and Ludovic Wesolowski and Anna Dyas and Cissy Yong and \{De Haan\}, Sanne and Jarno Drost and Stewart, \{Grant D.\} and Obenauf, \{Anna C.\} and Daniel Munoz-Espin and Sakari Vanharanta",

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month = dec,

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doi = "10.1038/s44321-025-00361-w",

language = "English",

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AU - Ge, Jianfeng

AU - Hirosue, Shoko

AU - Castillon, Leticia

AU - Patel, Saroor A.

AU - Wesolowski, Ludovic

AU - Dyas, Anna

AU - Yong, Cissy

AU - De Haan, Sanne

AU - Drost, Jarno

AU - Stewart, Grant D.

AU - Obenauf, Anna C.

AU - Munoz-Espin, Daniel

AU - Vanharanta, Sakari

PY - 2025/12/19

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AB - 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.

KW - CRISPR/Cas9 Screening

KW - HIF1A

KW - PROTAC

KW - Renal Cancer

KW - von Hippel-Lindau Tumor Suppressor (VHL)

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U2 - 10.1038/s44321-025-00361-w

DO - 10.1038/s44321-025-00361-w

M3 - Article

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JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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