# HIF-2α

Source: https://onco.cc/targets/hif2a/  
OnCo record `hif2a` (Target). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A master switch that kidney cancer cells leave permanently on when they lose the VHL gene; belzutifan blocks it.

## Summary

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.

## Fields

- Kind: Target
- Last checked: 2026-09-04
- Tags: transcription
- Symbol: EPAS1
- Class: transcription
- Biology: Transcription factor stabilised by VHL loss; drives VEGF, glycolysis, and proliferation genes.
- Where found: Clear-cell RCC; VHL disease; Pheochromocytoma

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/EPAS1
- Wikipedia: https://en.wikipedia.org/wiki/EPAS1

## Connected records

- cancers: [Clear cell renal cell carcinoma](https://onco.cc/cancers/clear-cell-rcc/), [Hereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127)](https://onco.cc/cancers/hereditary-ppgl/), [Metastatic pheochromocytoma and paraganglioma](https://onco.cc/cancers/metastatic-ppgl/), [Neuroendocrine tumours](https://onco.cc/cancers/neuroendocrine/), [Pancreatic neuroendocrine tumours](https://onco.cc/cancers/pancreatic-net/), [Pheochromocytoma and paraganglioma (PPGL)](https://onco.cc/cancers/pheochromocytoma-paraganglioma/), [Renal cell carcinoma](https://onco.cc/cancers/rcc/)
- drugs: [Belzutifan](https://onco.cc/drugs/belzutifan/)
- pathways: [Cancer metabolism](https://onco.cc/pathways/cancer-metabolism/), [Choline metabolism in cancer](https://onco.cc/pathways/choline-metabolism-in-cancer/), [Nutrient competition & metabolic immunosuppression](https://onco.cc/pathways/nutrient-competition-tme/), [Renal cell carcinoma (KEGG map)](https://onco.cc/pathways/renal-cell-carcinoma-signalling/), [Synthetic lethality: paired dependencies](https://onco.cc/pathways/synthetic-lethality-map/), [The angiogenic switch & tumour vessels](https://onco.cc/pathways/angiogenic-switch/), [The pre-metastatic niche](https://onco.cc/pathways/pre-metastatic-niche/), [Ubiquitin-proteasome system & protein homeostasis](https://onco.cc/pathways/ubiquitin-proteasome-system/), [VEGF angiogenesis](https://onco.cc/pathways/vegf-angiogenesis/), [VHL / HIF oxygen sensing](https://onco.cc/pathways/hif-vhl/)
- terms: [Angiogenesis](https://onco.cc/terms/angiogenesis/), [Hallmark: inducing or accessing vasculature](https://onco.cc/terms/inducing-angiogenesis/), [MEN1 and hereditary neuroendocrine syndromes](https://onco.cc/terms/men1-hereditary-net/), [Von Hippel-Lindau disease](https://onco.cc/terms/vhl-disease/)
- trials: [LITESPARK-005](https://onco.cc/trials/litespark-005/), [LITESPARK-022](https://onco.cc/trials/litespark-022/)
- technologies: [CAIX PET (89Zr-girentuximab)](https://onco.cc/technologies/caix-pet/), [Hypoxia-activated prodrugs](https://onco.cc/technologies/hypoxia-activated-therapy/)
- ideas: [CAIX theranostics: 89Zr-girentuximab PET and 177Lu/225Ac-girentuximab therapy](https://onco.cc/ideas/idea-caix-theranostics/)
- people: [Laurence Albiges](https://onco.cc/people/laurence-albiges/), [Toni K. Choueiri](https://onco.cc/people/toni-choueiri/), [William G. Kaelin Jr.](https://onco.cc/people/william-kaelin/)
- institutions: [Harold C. Simmons Comprehensive Cancer Center, UT Southwestern](https://onco.cc/institutions/utsw-simmons/)
- targets: [HIF-1α (HIF1A)](https://onco.cc/targets/hif1a/)

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JSON: https://onco.cc/api/v1/entities/hif2a.json