{"entity":{"id":"hif2a","kind":"target","name":"HIF-2α","aka":[],"tldr":"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.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/EPAS1","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/EPAS1"}],"tags":["transcription"],"related":[],"cancers":["rcc"],"sections":[],"technologies":[],"targets":[],"drugs":["belzutifan"],"companies":[],"institutions":[],"pathways":["hif-vhl","renal-cell-carcinoma-signalling"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"symbol":"EPAS1","role":[],"sources":[],"specificity":"tumour-associated","distribution":"one-type","specificityNote":"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.)","specificitySources":[{"label":"Human Protein Atlas EPAS1 tissue","url":"https://www.proteinatlas.org/ENSG00000116016-EPAS1/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Human Protein Atlas EPAS1 pathology","url":"https://www.proteinatlas.org/ENSG00000116016-EPAS1/pathology","note":"patients per staining level per cancer type (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000116016 associations","url":"https://platform.opentargets.org/target/ENSG00000116016/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:3374","ensembl":"ENSG00000116016","uniprot":"Q99814","entrez":"2034","firstDescribed":1997,"firstDescribedBasis":"sequence","firstDescribedNote":"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\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/9000051/","biology":"Transcription factor stabilised by VHL loss; drives VEGF, glycolysis, and proliferation genes.","whereFound":["Clear-cell RCC","VHL disease","Pheochromocytoma"],"targetClass":"transcription","prevalence":[{"cancerId":"rcc","pct":"85-90","measure":"VHL inactivation in clear-cell RCC","source":"https://www.cbioportal.org/study/summary?id=kirc_tcga_pan_can_atlas_2018"}]},"route":"/targets/hif2a/","neighbours":{"cancer":[{"id":"clear-cell-rcc","kind":"cancer","name":"Clear cell renal cell carcinoma","route":"/cancers/clear-cell-rcc/"},{"id":"hereditary-ppgl","kind":"cancer","name":"Hereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127)","route":"/cancers/hereditary-ppgl/"},{"id":"metastatic-ppgl","kind":"cancer","name":"Metastatic pheochromocytoma and paraganglioma","route":"/cancers/metastatic-ppgl/"},{"id":"neuroendocrine","kind":"cancer","name":"Neuroendocrine tumours","route":"/cancers/neuroendocrine/"},{"id":"pancreatic-net","kind":"cancer","name":"Pancreatic neuroendocrine tumours","route":"/cancers/pancreatic-net/"},{"id":"pheochromocytoma-paraganglioma","kind":"cancer","name":"Pheochromocytoma and paraganglioma (PPGL)","route":"/cancers/pheochromocytoma-paraganglioma/"},{"id":"rcc","kind":"cancer","name":"Renal cell carcinoma","route":"/cancers/rcc/"}],"drug":[{"id":"belzutifan","kind":"drug","name":"Belzutifan","route":"/drugs/belzutifan/"}],"pathway":[{"id":"cancer-metabolism","kind":"pathway","name":"Cancer metabolism","route":"/pathways/cancer-metabolism/"},{"id":"choline-metabolism-in-cancer","kind":"pathway","name":"Choline metabolism in cancer","route":"/pathways/choline-metabolism-in-cancer/"},{"id":"nutrient-competition-tme","kind":"pathway","name":"Nutrient competition & metabolic immunosuppression","route":"/pathways/nutrient-competition-tme/"},{"id":"renal-cell-carcinoma-signalling","kind":"pathway","name":"Renal cell carcinoma (KEGG map)","route":"/pathways/renal-cell-carcinoma-signalling/"},{"id":"synthetic-lethality-map","kind":"pathway","name":"Synthetic lethality: paired dependencies","route":"/pathways/synthetic-lethality-map/"},{"id":"angiogenic-switch","kind":"pathway","name":"The angiogenic switch & tumour vessels","route":"/pathways/angiogenic-switch/"},{"id":"pre-metastatic-niche","kind":"pathway","name":"The pre-metastatic niche","route":"/pathways/pre-metastatic-niche/"},{"id":"ubiquitin-proteasome-system","kind":"pathway","name":"Ubiquitin-proteasome system & protein homeostasis","route":"/pathways/ubiquitin-proteasome-system/"},{"id":"vegf-angiogenesis","kind":"pathway","name":"VEGF angiogenesis","route":"/pathways/vegf-angiogenesis/"},{"id":"hif-vhl","kind":"pathway","name":"VHL / HIF oxygen sensing","route":"/pathways/hif-vhl/"}],"term":[{"id":"angiogenesis","kind":"term","name":"Angiogenesis","route":"/terms/angiogenesis/"},{"id":"inducing-angiogenesis","kind":"term","name":"Hallmark: inducing or accessing vasculature","route":"/terms/inducing-angiogenesis/"},{"id":"men1-hereditary-net","kind":"term","name":"MEN1 and hereditary neuroendocrine syndromes","route":"/terms/men1-hereditary-net/"},{"id":"vhl-disease","kind":"term","name":"Von Hippel-Lindau disease","route":"/terms/vhl-disease/"}],"trial":[{"id":"litespark-005","kind":"trial","name":"LITESPARK-005","route":"/trials/litespark-005/"},{"id":"litespark-022","kind":"trial","name":"LITESPARK-022","route":"/trials/litespark-022/"}],"technology":[{"id":"caix-pet","kind":"technology","name":"CAIX PET (89Zr-girentuximab)","route":"/technologies/caix-pet/"},{"id":"hypoxia-activated-therapy","kind":"technology","name":"Hypoxia-activated prodrugs","route":"/technologies/hypoxia-activated-therapy/"}],"idea":[{"id":"idea-caix-theranostics","kind":"idea","name":"CAIX theranostics: 89Zr-girentuximab PET and 177Lu/225Ac-girentuximab therapy","route":"/ideas/idea-caix-theranostics/"}],"person":[{"id":"laurence-albiges","kind":"person","name":"Laurence Albiges","route":"/people/laurence-albiges/"},{"id":"toni-choueiri","kind":"person","name":"Toni K. Choueiri","route":"/people/toni-choueiri/"},{"id":"william-kaelin","kind":"person","name":"William G. Kaelin Jr.","route":"/people/william-kaelin/"}],"institution":[{"id":"utsw-simmons","kind":"institution","name":"Harold C. Simmons Comprehensive Cancer Center, UT Southwestern","route":"/institutions/utsw-simmons/"}],"target":[{"id":"hif1a","kind":"target","name":"HIF-1α (HIF1A)","route":"/targets/hif1a/"}]}}