Targeting renal cell carcinoma with a HIF-2 antagonist
Open accessAbstract
Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel-Lindau tumour suppressor gene (VHL). Because no other gene is mutated as frequently in ccRCC and VHL mutations are truncal, VHL inactivation is regarded as the governing event. VHL loss activates the HIF-2 transcription factor, and constitutive HIF-2 activity restores tumorigenesis in VHL-reconstituted ccRCC cells. HIF-2 has been implicated in angiogenesis and multiple other processes, but angiogenesis is the main target of drugs such as the tyrosine kinase inhibitor sunitinib. HIF-2 has been regarded as undruggable. Here we use a tumourgraft/patient-derived xenograft platform to evaluate PT2399, a selective HIF-2 antagonist that was identified using a structure-based design approach. PT2399 dissociated HIF-2 (an obligatory heterodimer of HIF-2α-HIF-1β) in human ccRCC cells and suppressed tumorigenesis in 56% (10 out of 18) of such lines. PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumours, and was better tolerated. Unexpectedly, some VHL-mutant ccRCCs were resistant to PT2399. Resistance occurred despite HIF-2 dissociation in tumours and evidence of Hif-2 inhibition in the mouse, as determined by suppression of circulating erythropoietin, a HIF-2 target and possible pharmacodynamic marker. We identified a HIF-2-dependent gene signature in sensitive tumours. Gene expression was largely unaffected by PT2399 in resistant tumours, illustrating the specificity of the drug. Sensitive tumours exhibited a distinguishing gene expression signature and generally higher levels of HIF-2α. Prolonged PT2399 treatment led to resistance. We identified binding site and second site suppressor mutations in HIF-2α and HIF-1β, respectively. Both mutations preserved HIF-2 dimers despite treatment with PT2399. Finally, an extensively pretreated patient whose tumour had given rise to a sensitive tumourgraft showed disease control for more than 11 months when treated with a close analogue of PT2399, PT2385. We validate HIF-2 as a target in ccRCC, show that some ccRCCs are HIF-2 independent, and set the stage for biomarker-driven clinical trials.
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PT2399 inhibited tumor growth in most human patient-derived xenografts and had stronger anti-tumor activity than sunitinib.
“PT2399 suppressed tumor growth in most human patient derived xenografts (PDXs) with greater anti-tumor activity than that of the tyrosine kinase inhibitor (TKI), sunitinib [22].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [22]
HIF-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 [81]
PT2399 selectively disrupts heterodimerization of HIF-2α and HIF-1β.
“PT2399 selectively disrupts the heterodimerization of HIF‐2α and HIF‐1β.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [159]
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- Authors
- Chen, W., Hill, H., Christie, A., Kim, M. S., Holloman, E., Pavia-Jimenez, A., Homayoun, F., Ma, Y., Patel, N., Yell, P., Hao, G., Yousuf, Q., Joyce, A., Pedrosa, I., Geiger, H., Zhang, H., Chang, J., Gardner, K. H., Bruick, R. K., Reeves, C., Hwang, T. H., Courtney, K., Frenkel, E., Sun, X., Zojwalla, N., Wong, T., Rizzi, J. P., Wallace, E. M., Josey, J. A., Xie, Y., Xie, X.-J., Kapur, P., McKay, R. M., & Brugarolas, J.
- Affiliations
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Harold C. Simmons Comprehensive Cancer Center (US)
- Parkland Health & Hospital System (US)
- The University of Texas Southwestern Medical Center (US)
- New York Genome Center (US)
- The Graduate Center, CUNY (US)
- Corresponding author
- Brugarolas, James
- ORCID
- Venue
- Nature
- Published
- 2016-09-05
- Volume
- 539
- Issue
- 7627
- Pages
- 112-117
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5340502
- OpenAlex
- W2513249090
- Cited by
- 709
- References
- 39
- Citations by year
- 2026: 53 · 2025: 60 · 2024: 64 · 2023: 59 · 2022: 85 · 2021: 90 · 2020: 86 · 2019: 71 · 2018: 74 · 2017: 54 · 2016: 12
- FWCI
- 29.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (UL1TR001105)
- National Cancer Institute (R01CA154475, R01CA175754, P50CA196516, P30CA142543)
- National Center for Advancing Translational Sciences
- 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
- HIF-2α inhibitor, clear cell renal cell carcinoma, VHL, patient-derived xenografts, predictive biomarkers, drug resistance, sunitinib, tumor angiogenesis, metastatic renal cell carcinoma, tumor regression
- MeSH terms
- Sunitinib, Endothelial PAS Domain-Containing Protein 1, Animals, Binding Sites, Carcinoma, Renal Cell, Cell Transformation, Neoplastic, Erythropoietin, Female, Humans, Indans, Indoles, Kidney Neoplasms, Male, Mutation, Pyrroles, Sulfones, Reproducibility of Results, Gene Expression Regulation, Neoplastic, Mice, SCID, Mice, Inbred NOD, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Aryl Hydrocarbon Receptor Nuclear Translocator, Basic Helix-Loop-Helix Proteins, Molecular Targeted Therapy
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