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A master switch that kidney cancer cells leave permanently on when they lose the VHL gene; belzutifan blocks it.
HIF-2α (EPAS1) is a transcription factor normally degraded by VHL; when VHL is lost, as in roughly 85 to 90 percent of clear-cell renal cell carcinomas, HIF-2α is permanently stabilised and drives VEGF, glycolysis and proliferation genes. Belzutifan (Welireg) binds the HIF-2α PAS-B pocket and prevents its pairing with ARNT. It is approved in VHL disease-associated tumours, in advanced RCC after immunotherapy and a VEGF tyrosine kinase inhibitor (LITESPARK-005), and from 2026 as adjuvant therapy with pembrolizumab in clear-cell RCC; it is also approved in pheochromocytoma and paraganglioma. Anaemia and hypoxia, which follow directly from suppressing erythropoietin, are the expected on-target effects. Combinations with VEGF inhibitors and immunotherapy in earlier lines are under study. It is the master switch kidney cancer leaves on, and belzutifan turns it down.
In plain words · A master switch that kidney cancer cells leave permanently on when they lose the VHL gene; belzutifan blocks it.
A master switch that kidney cancer cells leave permanently on when they lose the VHL gene; belzutifan blocks it.
Transcription factor stabilised by VHL loss; drives VEGF, glycolysis, and proliferation genes.
1 product aims at HIF-2α: small molecules. Transcription factors have no pocket to plug, so drugs either degrade them or block the partner protein they need to dock on DNA.
Tumour-associated overexpression: HPA finds the RNA cancer enhanced in cancer (Kidney Renal Clear Cell Carcinoma (TCGA)) and tissue enhanced in normal lung, placenta, so the tumour and the normal tissue it comes from share the target and the medicine relies on the difference in level. HPA EPAS1: RNA tissue enhanced (lung 389 nTPM, placenta 419 nTPM); blood lineage lineage enriched (granulocytes 21 nTPM); no normal tissue stained high. Distribution: 1 cancer family in the corpus carries a prevalence row, label threshold or catalogue link for it (Renal cell carcinoma); approvals of single-target medicines aimed at it also list Brain and spinal cord tumours (all types), Neuroendocrine tumours, Pheochromocytoma and paraganglioma (PPGL), not counted; Open Targets associates it with 1 specific cancer type at or above 0.5 (renal cell carcinoma). (Rule 7 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas EPAS1 tissue; Human Protein Atlas EPAS1 pathology; Open Targets ENSG00000116016 associations
First described 1997. Earliest sequence paper UniProt cites for the protein: Tian et al, Genes Dev, 1997, "Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells". Source.
Transcription factor stabilised by VHL loss; drives VEGF, glycolysis, and proliferation genes.
RNA: tissue enhanced (lung 389 nTPM, placenta 419 nTPM), detected in all normal tissues. Blood: lineage enriched (granulocytes 21 nTPM).
No normal tissue stained high.
RNA cancer enhanced: Kidney Renal Clear Cell Carcinoma 231 pTPM.
No cancer sample stained medium or high.
HPA EPAS1 tissue · HPA EPAS1 pathology · HPA protein class: FDA approved drug targets
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Renal cell carcinoma | 85-90% | VHL inactivation in clear-cell RCC | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Belzutifan is the first HIF-2α inhibitor, born from Nobel-winning biology, and is now approved after kidney cancer surgery with pembrolizumab.
Query for this target: (TITLE:"HIF-2α" OR ABSTRACT:"HIF-2α" OR TITLE:"EPAS1" OR ABSTRACT:"EPAS1") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about HIF-2α, not a curated reading list.
Shares VHL / HIF oxygen sensing, Renal cell carcinoma (KEGG map), Ubiquitin-proteasome system & protein homeostasis, Pheochromocytoma and paraganglioma (PPGL).
Shares Hereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127), Metastatic pheochromocytoma and paraganglioma, Pheochromocytoma and paraganglioma (PPGL), Belzutifan.
Shares LITESPARK-022, CAIX PET (89Zr-girentuximab), Belzutifan, Renal cell carcinoma.
Shares HIF-1α (HIF1A), Choline metabolism in cancer, Renal cell carcinoma (KEGG map), Pancreatic neuroendocrine tumours.
Shares HIF-1α (HIF1A), VHL / HIF oxygen sensing, Renal cell carcinoma (KEGG map), Renal cell carcinoma.
Shares CAIX PET (89Zr-girentuximab), Clear cell renal cell carcinoma, Renal cell carcinoma.
Shares CAIX theranostics: 89Zr-girentuximab PET and 177Lu/225Ac-girentuximab therapy, CAIX PET (89Zr-girentuximab).
Shares Hereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127), Metastatic pheochromocytoma and paraganglioma, Pheochromocytoma and paraganglioma (PPGL), Pancreatic neuroendocrine tumours.