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Von Hippel–Lindau protein signalling in clear cell renal cell carcinoma

Nature Reviews Urology (2024)Cite this article

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Abstract

The distinct pathological and molecular features of kidney cancer in adaptation to oxygen homeostasis render this malignancy an attractive model for investigating hypoxia signalling and potentially developing potent targeted therapies. Hypoxia signalling has a pivotal role in kidney cancer, particularly within the most prevalent subtype, known as renal cell carcinoma (RCC). Hypoxia promotes various crucial pathological processes, such as hypoxia-inducible factor (HIF) activation, angiogenesis, proliferation, metabolic reprogramming and drug resistance, all of which contribute to kidney cancer development, growth or metastasis formation. A substantial portion of kidney cancers, in particular clear cell RCC (ccRCC), are characterized by a loss of function of Von Hippel–Lindau tumour suppressor (VHL), leading to the accumulation of HIF proteins, especially HIF2α, a crucial driver of ccRCC. Thus, therapeutic strategies targeting pVHL–HIF signalling have been explored in ccRCC, culminating in the successful development of HIF2α-specific antagonists such as belzutifan (PT2977), an FDA-approved drug to treat VHL-associated diseases including advanced-stage ccRCC. An increased understanding of hypoxia signalling in kidney cancer came from the discovery of novel VHL protein (pVHL) targets, and mechanisms of synthetic lethality with VHL mutations. These breakthroughs can pave the way for the development of innovative and potent combination therapies in kidney cancer.

Key points

  • The tumour suppressor Von Hippel–Lindau protein (pVHL), which has vital functions in proteasomal degradation, is predominantly lost or mutated in kidney cancer.

  • The pVHL–hypoxia-inducible factor (HIF) axis is a major oncogenic signalling pathway in clear cell renal cell carcinoma (ccRCC).

  • New agents that target HIF2α, such as belzutifan, have improved clinical outcomes in patients with ccRCC.

  • A group of newly identified pVHL downstream oncogenes provides potential novel therapeutic targets for ccRCC.

  • Targeting pathways showing synthetic lethality with VHL loss is an attractive and alternative strategy for treating ccRCC.

  • Combination therapies with hypoxia signalling inhibitors plus other therapeutic agents hold potential for the treatment of advanced or metastatic ccRCC.

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Fig. 1: pVHL–HIF signalling pathway and therapeutic interventions targeting HIF2 in ccRCC.
Fig. 2: Targeting synthetic lethality with VHL loss in ccRCC.

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Acknowledgements

Kidney cancer research in Zhang lab is supported by the National Cancer Institute (R01CA211732 and R01CA284591), Department of Defense Kidney Cancer Research Program (W81XWH1910813) and Cancer Prevention and Research Institute of Texas (CPRIT, RR190058 to Q.Z.). Q.Z. was an American Cancer Society Research Scholar, CPRIT Scholar in Cancer Research, V Scholar, Kimmel Scholar, Susan G. Komen Career Catalyst awardee and Mary Kay Foundation awardee. Q.Z. was also previously supported by Kidney Cancer Research Alliance (KCCure).

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  1. These authors contributed equally: Chengheng Liao, Lianxin Hu.

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  1. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Chengheng Liao, Lianxin Hu & Qing Zhang

  2. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Qing Zhang

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C.L. and L.H. researched data for the article. All authors contributed substantially to discussion of the content. All authors. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Liao, C., Hu, L. & Zhang, Q. Von Hippel–Lindau protein signalling in clear cell renal cell carcinoma. Nat Rev Urol (2024). https://doi.org/10.1038/s41585-024-00876-w

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