On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models
Open accessAbstract
Clear cell renal cell carcinoma, the most common form of kidney cancer, is usually linked to inactivation of the pVHL tumour suppressor protein and consequent accumulation of the HIF-2α transcription factor (also known as EPAS1). Here we show that a small molecule (PT2399) that directly inhibits HIF-2α causes tumour regression in preclinical mouse models of primary and metastatic pVHL-defective clear cell renal cell carcinoma in an on-target fashion. pVHL-defective clear cell renal cell carcinoma cell lines display unexpectedly variable sensitivity to PT2399, however, suggesting the need for predictive biomarkers to be developed to use this approach optimally in the clinic.
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Those studies used 786-0 cells, which are pVHL-deficient RCC cells lacking HIF-1α, and may have adapted to depend selectively on HIF-2α.
“However, these studies were performed using 786–0 cells, which are pVHL deficient RCC cells that intrinsically lack HIF-1α expression, and may have thus adapted to selectively depend on HIF-2α [26–28].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [27]
The supplied Abstract passages identify 786-O as VHL-deficient ccRCC cells lacking wild-type HIF-1α and show HIF-2α-dependent growth. But the paper also studied other cell lines and explicitly says HIF-2α dependence is not linked to HIF-1α status; it does not support the proposed adaptation from HIF-1α loss. Page numbers were not supplied. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe initial proposal that HIF-2α is pro-tumorigenic came from studies where HIF-2α overexpression, but not HIF-1α, blocked pVHL re-expression from inhibiting xenograft formation, and HIF-2α shRNA prevented xenograft formation.
“Specifically, the pro-tumorigenic role of HIF-2α was initially proposed based on studies showing that overexpression of HIF-2α, but not HIF-1α, abrogated the ability of pVHL re-expression to inhibit xenograft formation, and the converse that HIF-2α shRNA prevented tumor xenograft formation [26–28].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [27]
The paper’s main text (indexed under Abstract; page unavailable) says that inhibiting A498 tumors was consistent with earlier effects of HIF-2α shRNAs, supporting the claim’s general point that HIF-2α promotes tumor growth. It does not state that shRNA prevented xenograft formation or describe the claimed comparison in which HIF-2α, but not HIF-1α, overexpression overcame inhibition by pVHL re-expression. (LLM, conf=0.82)
Experimental — accuracy not yet measuredHIF-2α can be targeted by selective inhibitors, and these molecules effectively suppress cancer cell growth and tumor angiogenesis characteristics in ccRCC.
“Indeed, recent studies have shown that HIF-2α can be targeted by selective inhibitors and have indicated that these molecules effectively suppress cancer cell growth and tumor angiogenesis characteristics in ccRCC79–82.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [82]
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Cites
HIF-2α Promotes Hypoxic Cell Proliferation by Enhancing c-Myc Transcriptional Activity
Gordan, J. D., Bertout, J. A., Hu, C.-J., Diehl, J. A., & Simon, M. C. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.02.006 · Cited by 781 · see citing works
Targeting renal cell carcinoma with a HIF-2 antagonist
Chen, W., Hill, H., Christie, A., Kim, M. S., Holloman, E., Pavia-Jimenez, A., Homayoun, F., Ma, Y., Patel, N., Yell, P., et al. (2016) · Nature · doi:10.1038/nature19796 · Cited by 709 · see citing works
Self-citationTumour suppression by the human von Hippel-Lindau gene product
Iliopoulos, O., Kibel, A. S., Gray, S. G., & Kaelin, W. G. (1995) · Nature Medicine · doi:10.1038/nm0895-822 · Cited by 696 · see citing works
Self-citationInhibition of HIF2α Is Sufficient to Suppress pVHL-Defective Tumor Growth
Kondo, K., Kim, W. Y., Lechpammer, M., & Kaelin, W. G. (2003) · PLoS Biology · doi:10.1371/journal.pbio.0000083 · Cited by 611 · see citing works
Self-citationHIF-α effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma
Gordan, J. D., Lal, P., Dondeti, V. R., Letrero, R., Parekh, K. N., Oquendo, C. E., Greenberg, R. A., Flaherty, K. T., Rathmell, W. K., Keith, B., et al. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.10.016 · Cited by 493 · see citing works
Genetic and Functional Studies Implicate <i>HIF1</i> α as a 14q Kidney Cancer Suppressor Gene
Shen, C., Beroukhim, R., Schumacher, S. E., Zhou, J., Chang, M., Signoretti, S., & Kaelin, W. G. (2011) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0098 · Cited by 413 · see citing works
Self-citationA Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma
Wallace, E. M., Rizzi, J. P., Han, G., Wehn, P. M., Cao, Z., Du, X., Cheng, T., Czerwinski, R. M., Dixon, D. D., Goggin, B. S., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-0473 · Cited by 336 · see citing works
Self-citationAllosteric inhibition of hypoxia inducible factor-2 with small molecules
Scheuermann, T. H., Li, Q., Ma, H.-W., Key, J., Zhang, L., Chen, R., Garcia, J. A., Naidoo, J., Longgood, J., Frantz, D. E., et al. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1185 · Cited by 315 · see citing works
Self-citationArtificial ligand binding within the HIF2α PAS-B domain of the HIF2 transcription factor
Scheuermann, T. H., Tomchick, D. R., Machius, M., Guo, Y., Bruick, R. K., & Gardner, K. H. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808092106 · Cited by 301 · see citing works
Self-citationEpigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer
Vanharanta, S., Shu, W., Brenet, F., Hakimi, A. A., Heguy, A., Viale, A., Reuter, V. E., Hsieh, J. J.-D., Scandura, J. M., & Massagué, J. (2013) · Nature Medicine · doi:10.1038/nm.3029 · Cited by 215 · see citing works
HIF2α inhibition promotes p53 pathway activity, tumor cell death, and radiation responses
Bertout, J. A., Majmundar, A. J., Gordan, J. D., Lam, J. C., Ditsworth, D., Keith, B., Brown, E. J., Nathanson, K. L., & Simon, M. C. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0907357106 · Cited by 196 · see citing works
Development of Inhibitors of the PAS-B Domain of the HIF-2α Transcription Factor
Rogers, J. L., Bayeh, L., Scheuermann, T. H., Longgood, J. C., Key, J., Naidoo, J., Melito, L. M., Shokri, C., Frantz, D. E., Bruick, R. K., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm301847z · Cited by 139 · see citing works
Self-citationRoberts, A. M., Watson, I. R., Evans, A. J., Foster, D. A., Irwin, M. S., & Ohh, M. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-1770 · Cited by 88 · see citing works
Fay, A. P., de Velasco, G., Ho, T. H., Allen, E. M. V., Murray, B. A., Albiges, L. K., Signoretti, S., Hakimi, A. A., Stanton, M., Joaquim Bellmunt, B., et al. (2016) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2016.0086 · Cited by 41 · see citing works
Self-citationMolecular Biology of Kidney Cancer
Kaelin, W. G. (2015) · Springer eBooks · doi:10.1007/978-3-319-17903-2_3 · Cited by 12 · see citing works
Self-citation
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Research works printed but not linked: 2
- [1]Kaelin W Kidney Cancer: Principles and Practice 3 31 57 Springer International Publishing 2015
- [6]Wallace EM Anti-Tumor Activity of a Small Molecule Hypoxia Inducible Factor-2α Antagonist in Models of Renal Cell Carcinoma Cancer Research Under Review
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Chen, Z., Han, F., Du, Y., Shi, H., & Zhou, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01332-8 · Cited by 1,612 · see citing works
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Zou, Y., Palte, M. J., Deik, A. A., Li, H., Eaton, J. K., Wang, W., Tseng, Y.-Y., Deasy, R., Kost-Alimova, M., Dančík, V., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09277-9 · Cited by 887 · see citing works
Self-citationTargeting renal cell carcinoma with a HIF-2 antagonist
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Self-citationRegulation of Immunity and Inflammation by Hypoxia in Immunological Niches
Taylor, C. T., & Colgan, S. P. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.103 · Cited by 713 · see citing works
Belzutifan for Renal Cell Carcinoma in von Hippel–Lindau Disease
Jonasch, E., Donskov, F., Iliopoulos, O., Rathmell, W. K., Narayan, V. K., Maughan, B. L., Oudard, S., Else, T., Maranchie, J. K., Welsh, S. J., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2103425 · Cited by 714 · see citing works
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Luo, Z., Tian, M., Yang, G., Tan, Q., Chen, Y., Li, G., Zhang, Q., Li, Y., Wan, P., & Wu, J. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01080-1 · Cited by 499 · see citing works
Targeting the HIF2–VEGF axis in renal cell carcinoma
Choueiri, T. K., & Kaelin, W. G. (2020) · Nature Medicine · doi:10.1038/s41591-020-1093-z · Cited by 477 · see citing works
Self-citationYoo, H. C., Park, S. J., Nam, M., Kang, J., Kim, K., Yeo, J. H., Kim, J.-K., Heo, Y., Lee, H. S., Lee, M. Y., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2019.11.020 · Cited by 449 · see citing works
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Das, N. K., Schwartz, A. J., Barthel, G., Inohara, N., Liu, Q., Sankar, A., Hill, D. R., Ma, X., Lamberg, O., Schnizlein, M. K., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2019.10.005 · Cited by 331 · see citing works
Mechanisms of hypoxia signalling: new implications for nephrology
Schödel, J., & Ratcliffe, P. J. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0182-z · Cited by 309 · see citing works
Hoefflin, R., Harlander, S., Schäfer, S., Metzger, P., Kuo, F., Schönenberger, D., Adlesic, M., Peighambari, A., Seidel, P., Chen, C.-Y., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17873-3 · Cited by 292 · see citing works
Pharmacologic Targeting of Hypoxia-Inducible Factors
Semenza, G. L. (2019) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010818-021637 · Cited by 288 · see citing works
Revisiting the HIF switch in the tumor and its immune microenvironment.
Cowman, S. J., & Koh, M. Y. (2022) · Trends in Cancer · doi:10.1016/j.trecan.2021.10.004 · Cited by 256 · see citing works
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Singhal, R., Mitta, S. R., Das, N. K., Kerk, S. A., Sajjakulnukit, P., Solanki, S., Andren, A., Kumar, R., Olive, K. P., Banerjee, R., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci143691 · Cited by 215 · see citing works
Tumor hypoxia: From basic knowledge to therapeutic implications
Liao, C., Liu, X., Zhang, C., & Zhang, Q. (2023) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.12.011 · Cited by 223 · see citing works
Courtney, K. D., Ma, Y., Diaz de Leon, A., Christie, A., Xie, Z., Woolford, L., Singla, N., Joyce, A., Hill, H., Madhuranthakam, A. J., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-1459 · Cited by 188 · see citing works
Combined mutation in Vhl, Trp53 and Rb1 causes clear cell renal cell carcinoma in mice
Harlander, S., Schönenberger, D., Toussaint, N. C., Prummer, M., Catalano, A., Brandt, L., Moch, H., Wild, P. J., & Frew, I. J. (2017) · Nature Medicine · doi:10.1038/nm.4343 · Cited by 143 · see citing works
Yan, Y., He, M., Zhao, L., Wu, H., Zhao, Y., Han, L., Wei, B., Ye, D., Lv, X., Wang, Y., et al. (2022) · Cell Death & Differentiation · doi:10.1038/s41418-022-00963-8 · Cited by 101 · see citing works
Macrophage HIF-1α Is an Independent Prognostic Indicator in Kidney Cancer
Cowman, S. J., Fuja, D. G., Liu, X.-D., Tidwell, R. S. S., Kandula, N., Sirohi, D., Agarwal, A. M., Emerson, L. L., Tripp, S. R., Mohlman, J. S., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-3890 · Cited by 76 · see citing works
HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy
Jiang, Q., Braun, D. A., Clauser, K. R., Ramesh, V., Shirole, N. H., Duke-Cohan, J. E., Nabilsi, N., Kramer, N. J., Forman, C., Lippincott, I. E., et al. (2025) · Cell · doi:10.1016/j.cell.2025.01.046 · Cited by 68 · see citing works
Self-citationHypoxia-inducible factor in cancer: from pathway regulation to therapeutic opportunity
Ortmann, B. M. (2024) · BMJ Oncology · doi:10.1136/bmjonc-2023-000154 · Cited by 67 · see citing works
Hypoxia inducible factor (HIF) as a model for studying inhibition of protein–protein interactions
Burslem, G. M., Kyle, H. F., Nelson, A., Edwards, T. A., & Wilson, A. J. (2017) · Chemical Science · doi:10.1039/c7sc00388a · Cited by 39 · see citing works
Persson, C. U., von Stedingk, K., Fredlund, E., Bexell, D., Påhlman, S., Wigerup, C., & Mohlin, S. (2020) · Experimental Cell Research · doi:10.1016/j.yexcr.2020.111845 · Cited by 37 · see citing works
Specific inhibition of HIF activity: can peptides lead the way?
Mylonis, I., Chachami, G., & Simos, G. (2021) · Cancers · doi:10.3390/cancers13030410 · Cited by 21 · see citing works
HIF1α is not a target of 14q deletion in clear cell renal cancer
Shenoy, N. (2020) · Scientific Reports · doi:10.1038/s41598-020-74631-7 · Cited by 14 · see citing works
- Authors
- Cho, H., Du, X., Rizzi, J. P., Liberzon, E., Chakraborty, A. A., Gao, W., Carvo, I., Signoretti, S., Bruick, R. K., Josey, J. A., Wallace, E. M., & Kaelin, W. G.
- Affiliations
- Brigham and Women's Hospital (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Wallace, Eli M.
- Kaelin, William G.
- ORCID
- Venue
- Nature
- Published
- 2016-09-05
- Volume
- 539
- Issue
- 7627
- Pages
- 107-111
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5499381
- OpenAlex
- W2510079645
- Cited by
- 451
- References
- 15
- Citations by year
- 2026: 31 · 2025: 39 · 2024: 42 · 2023: 41 · 2022: 48 · 2021: 56 · 2020: 49 · 2019: 52 · 2018: 46 · 2017: 36 · 2016: 11
- FWCI
- 20.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (P50CA101942, R35CA210068)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- clear cell renal cell carcinoma, EPAS1, small molecule inhibitors, tumor regression, predictive biomarkers, drug resistance, metastatic renal cell carcinoma
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Carcinoma, Renal Cell, Disease Models, Animal, Humans, Indans, Kidney Neoplasms, Models, Biological, Neoplasm Metastasis, Sulfones, Transcription, Genetic, Gene Expression Regulation, Neoplastic, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Von Hippel-Lindau Tumor Suppressor Protein, Biomarkers, Pharmacological
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