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  • Perspective
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Targeting the HIF2–VEGF axis in renal cell carcinoma

Nature Medicine volume 26, pages 1519–1530 (2020)Cite this article

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An Author Correction to this article was published on 28 August 2024

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Abstract

Insights into the role of the tumor suppressor pVHL in oxygen sensing motivated the testing of drugs that target the transcription factor HIF or HIF-responsive growth factors, such as VEGF, for the treatment of cancers caused by VHL inactivation, such as clear-cell renal cell carcinoma (ccRCC). Multiple VEGF inhibitors are now approved for the treatment of ccRCC, and a HIF2α inhibitor has advanced to phase 3 development for this disease. These inhibitors are now also increasingly combined with immune-checkpoint blockers. In this Perspective, we describe the understanding of the mechanisms of oxygen sensing and hypoxia signaling that resulted in the development of HIF2α-targeted therapies for patients with VHL-associated tumors. We also present future directions for extending the use of these therapies to other cancers.

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Fig. 2: Mechanisms of resistance.

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Acknowledgements

We acknowledge Z. Bakouny and K. Pels (Dana-Farber Cancer Institute) and N. Zojwalla (Peloton Therapeutics) for careful reading of this manuscript and useful suggestions.

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  1. Dana-Farber Cancer Institute, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Toni K. Choueiri & William G. Kaelin Jr

  2. Howard Hughes Medical Institute, Chevy Chase, MD, USA

    William G. Kaelin Jr

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T.K.C. reports receiving research support (institutional and personal) from AstraZeneca, Alexion, Bayer, Bristol Myers-Squibb/ER Squibb & Sons, Cerulean, Eisai, Foundation Medicine, Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, and Takeda; honoraria from AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol-Myers Squibb/ER Squibb & Sons, Cerulean, Eisai, Foundation Medicine, Exelixis, Genentech, Roche, Roche Products, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, Analysis Group, National Comprehensive Cancer Network, Michael J. Hennessy (MJH) Associates (healthcare communications company with several brands, such as OncLive, PeerView and PER), Research to Practice, L-path, Kidney Cancer journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, New England Journal of Medicine, Lancet Oncology, Heron Therapeutics and Lilly; has had a consulting or advisory role for AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol-Myers Squibb/ER Squibb & Sons, Cerulean, Eisai, Foundation Medicine, Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, National Comprehensive Cancer Network, Analysis Group, Pionyr and Tempest; owns stock in Pionyr and Tempest; and has received travel, accommodations, and expenses in relation to consulting, advisory roles or honoraria. W.G.K. is a board director at Lilly Pharmaceuticals, is a founder of Tango Therapeutics and Cedilla Therapeutics, is a Scientific Advisor at Nextech Invest, has ownership interest (including stock, patents, etc.) in Lilly, Tango Therapeutics, Nextech Invest and Cedilla Therapeutics, and is a consultant/advisory board member for Lilly Pharmaceuticals, Tango Therapeutics, Nextech Invest and Cedilla Therapeutics.

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Choueiri, T.K., Kaelin, W.G. Targeting the HIF2–VEGF axis in renal cell carcinoma. Nat Med 26, 1519–1530 (2020). https://doi.org/10.1038/s41591-020-1093-z

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