{"entity":{"id":"keap1","kind":"target","name":"KEAP1","aka":["kelch like ECH associated protein 1","Kelch-like ECH-associated protein 1","KIAA0132","MGC10630","MGC1114","MGC20887","MGC4407","MGC9454","INrf2","KLHL19"],"tldr":"KEAP1 (Kelch-like ECH-associated protein 1) is a gene whose normal job is to hold cell growth in check. The public catalogues list it as a drug target, an oncogene driver, a tumour suppressor and a biomarker, and clinical evidence ties its variants to diagnosis, prognosis or drug response. Tied to Lung cancer, Hepatocellular carcinoma, Nasopharyngeal carcinoma and 3 more.","summary":"Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates the response to oxidative stress by targeting NFE2L2/NRF2 for ubiquitination. KEAP1 acts as a key sensor of oxidative and electrophilic stress: in normal conditions, the BCR(KEAP1) complex mediates ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes. In response to oxidative stress, different electrophile metabolites trigger non-enzymatic covalent modifications of highly reactive cysteine residues in KEAP1, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes.\n\nCIViC holds 6 clinical evidence items and 0 assertions across 2 variants, naming Cisplatin/Pembrolizumab/Pemetrexed Regimen, Chemotherapy, Palliative Radiation Therapy and Durvalumab Regimen and others. Open Targets scores its association with cancer at 0.76 (direct and indirect evidence; datatypes clinical 0.14, literature 0.99, genetic association 0.18, somatic mutation 0.96, animal model 0.37). IntOGen calls it a driver in 14 cohorts (7 activating, 7 loss-of-function), covering Cholangiocarcinoma, Hepatocellular Carcinoma, Lung Adenocarcinoma, Lung Squamous Cell Carcinoma, Nasopharyngeal Carcinoma, Non-Small Cell Lung Cancer.","asOf":"2026-09-23","links":[{"label":"HGNC HGNC:23177","url":"https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:23177"},{"label":"UniProt Q14145","url":"https://www.uniprot.org/uniprotkb/Q14145/entry"},{"label":"NCBI Gene 9817","url":"https://www.ncbi.nlm.nih.gov/gene/9817"},{"label":"Ensembl ENSG00000079999","url":"https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000079999"}],"tags":["cancer-genes-wave"],"related":["civic","open-targets","intogen","stk11-keap1-loss"],"cancers":["lung-cancer","hcc","nasopharyngeal","neuroendocrine","nsclc","cholangiocarcinoma"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":["hepatocellular-carcinoma-signalling","keap1-nrf2"],"terms":["stk11-keap1"],"trials":["nct05276726","nct06008093"],"people":[],"bottlenecks":[],"keyPapers":["paper-arbour-kras-co-mutation-outcomes-ccr-2018","paper-ricciuti-stk11-keap1-kras-immunotherapy-jto-2022"],"journals":[],"dependsOn":[],"notes":["Written by scripts/fetch-cancer-genes.ts from CIViC, Open Targets, IntOGen, HGNC and UniProt; the function text is UniProt's, condensed and in UK spelling. Roles: Open Targets known-drug datatype score 0.14; IntOGen calls it an activating (Act) driver in 7 cohorts; IntOGen calls it a loss-of-function (LoF) driver in 7 cohorts; CIViC holds 6 clinical evidence items on its variants. Evidence tier \"clinical-evidence\" is the strongest of those signals.","Prevalence not recorded: none of the sources gives a positivity rate.","Lung cancer: inactivated in 11 to 18% of adenocarcinomas and 10.1% of squamous tumours, with the squamous half of the pathway broken through NFE2L2 degron hotspots instead (cBioPortal). In 330 KRAS-mutant patients, KEAP1 or NFE2L2 co-mutation was the only independent predictor of shorter survival (hazard ratio 1.96), shortened the duration of first chemotherapy and shortened survival from the start of immunotherapy (3.54) (Arbour 2018). Its first effect is metabolic: releasing NRF2 switches on an antioxidant programme that supports growth under oxidative and radiation stress."],"provenance":{"editedBy":"scripts/fetch-cancer-genes.ts (CIViC, Open Targets, IntOGen, HGNC, UniProt)","editedOn":"2026-09-23"},"symbol":"KEAP1","role":["drug-target","oncogene-driver","tumour-suppressor","biomarker"],"evidenceTier":"clinical-evidence","sources":[{"label":"HGNC HGNC:23177","url":"https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:23177","note":"approved symbol, name, aliases, locus and cross-references (hgnc_complete_set.txt)"},{"label":"UniProt Q14145","url":"https://www.uniprot.org/uniprotkb/Q14145/entry","note":"protein name, function text, keywords and locations (REST API)"},{"label":"CIViC gene KEAP1","url":"https://civicdb.org/features/7777","note":"6 evidence items, 0 assertions, 2 variants; diseases: Lung Non-small Cell Carcinoma (GraphQL API, CC0)"},{"label":"Open Targets ENSG00000079999","url":"https://platform.opentargets.org/target/ENSG00000079999/associations","note":"association with cancer (MONDO_0004992) 0.76; per-cancer scores at or above 0.5: non-small cell lung carcinoma 0.69, neuroendocrine neoplasm 0.52, lung cancer 0.72 (GraphQL API, CC0)"},{"label":"IntOGen KEAP1","url":"https://www.intogen.org/search?gene=KEAP1","note":"driver in 14 cohorts (Act 7, LoF 7); Compendium_Cancer_Genes.tsv release 20240920, CC0 1.0"}],"specificity":"tumour-specific","distribution":"many-types","specificityNote":"Tumour-specific alteration: the catalogues call it an oncogene driver (IntOGen cohort analysis finds it activated more often than chance) and a tumour suppressor (IntOGen finds it knocked out more often than chance), so the direction differs between cohorts but the alteration is somatic either way; what a medicine would aim at or exploit is the altered form or its loss, absent from normal cells; no corpus medicine is aimed at it yet. HPA KEAP1: RNA tissue enhanced (skeletal muscle 171 nTPM); high antibody staining in 8 normal tissues; highest cancer staining colorectal cancer (1 of 9 high). Distribution: 5 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Lung cancer (all types), Hepatocellular carcinoma, Nasopharyngeal carcinoma, Neuroendocrine tumours, Biliary tract cancer (all types)); Open Targets associates it with 3 specific cancer types at or above 0.5 (lung adenocarcinoma, non-small cell lung carcinoma, squamous cell lung carcinoma). (Rule 6 of scripts/fetch-target-specificity.ts.)","specificitySources":[{"label":"UniProt Q14145","url":"https://www.uniprot.org/uniprotkb/Q14145/entry","note":"protein name, function text, keywords and locations (REST API)"},{"label":"CIViC gene KEAP1","url":"https://civicdb.org/features/7777","note":"6 evidence items, 0 assertions, 2 variants; diseases: Lung Non-small Cell Carcinoma (GraphQL API, CC0)"},{"label":"IntOGen KEAP1","url":"https://www.intogen.org/search?gene=KEAP1","note":"driver in 14 cohorts (Act 7, LoF 7); Compendium_Cancer_Genes.tsv release 20240920, CC0 1.0"},{"label":"Human Protein Atlas KEAP1 tissue","url":"https://www.proteinatlas.org/ENSG00000079999-KEAP1/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000079999 associations","url":"https://platform.opentargets.org/target/ENSG00000079999/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:23177","ensembl":"ENSG00000079999","uniprot":"Q14145","entrez":"9817","firstDescribed":1995,"firstDescribedBasis":"sequence","firstDescribedNote":"Earliest sequence paper UniProt cites for the protein: Nagase et al, DNA Res, 1995, \"Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/8590280/","biology":"Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates the response to oxidative stress by targeting NFE2L2/NRF2 for ubiquitination. KEAP1 acts as a key sensor of oxidative and electrophilic stress: in normal conditions, the BCR(KEAP1) complex mediates ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes. In response to oxidative stress, different electrophile metabolites trigger non-enzymatic covalent modifications of highly reactive cysteine residues in KEAP1, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes. In response to selective autophagy, KEAP1 is sequestered in inclusion bodies following its interaction with SQSTM1/p62, leading to inactivation of the BCR(KEAP1) complex and activation of NFE2L2/NRF2. The BCR(KEAP1) complex also mediates ubiquitination of SQSTM1/p62, increasing SQSTM1/p62 sequestering activity and degradation. The BCR(KEAP1) complex also targets BPTF and PGAM5 for ubiquitination and degradation by the proteasome. Location: Cytoplasm; Nucleus (UniProt). Locus 19p13.2 (HGNC).","whereFound":["Lung cancer: Open Targets association 0.72 with lung cancer (MONDO_0008903)","Hepatocellular carcinoma: IntOGen driver in 2 cohorts (HCC)","Nasopharyngeal carcinoma: IntOGen driver in 1 cohort (NPC)","Neuroendocrine tumours: Open Targets association 0.52 with neuroendocrine neoplasm (MONDO_0019496)","Non-small-cell lung cancer: Open Targets association 0.69 with non-small cell lung carcinoma (MONDO_0005233); CIViC evidence names this disease","Biliary tract cancer: IntOGen driver in 1 cohort (CHOL)","Non-small-cell lung cancer: inactivating mutation 11-18%"],"targetClass":"tumor-suppressor","prevalence":[{"cancerId":"nsclc","pct":"11-18","measure":"Inactivating mutation","source":"https://www.cbioportal.org/study/summary?id=luad_mskcc_2023_met_organotropism","note":"cBioPortal: 400 of 2,653, 15.1%, in luad_mskcc_2023_met_organotropism; 153 of 915, 16.7%, in lung_msk_2017; 102 of 566, 18.0%, in luad_tcga_pan_can_atlas_2018; 40 of 230, 17.4%, in luad_tcga_pub; 12 of 110, 10.9%, in luad_cptac_2020; 197 of 2,621, 7.5%, in nsclc_ctdx_msk_2022; 13 of 302, 4.3%, in luad_oncosg_2020; 1 of 232, 0.4%, in lung_nci_2022. In the immunotherapy cohort, 53 of 240, 22.1% (cBioPortal nsclc_pd1_msk_2018); deleterious KEAP1 mutations were 231 of 1,202 assessable patients, 19.2% (Ricciuti 2022)."}]},"route":"/targets/keap1/","neighbours":{"collection":[{"id":"civic","kind":"collection","name":"CIViC","route":"/collections/civic/"},{"id":"intogen","kind":"collection","name":"IntOGen","route":"/collections/intogen/"},{"id":"open-targets","kind":"collection","name":"Open Targets Platform","route":"/collections/open-targets/"}],"biomarker":[{"id":"stk11-keap1-loss","kind":"biomarker","name":"STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma","route":"/biomarkers/stk11-keap1-loss/"}],"cancer":[{"id":"cholangiocarcinoma","kind":"cancer","name":"Biliary tract cancer (cholangiocarcinoma)","route":"/cancers/cholangiocarcinoma/"},{"id":"hcc","kind":"cancer","name":"Hepatocellular carcinoma","route":"/cancers/hcc/"},{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"nasopharyngeal","kind":"cancer","name":"Nasopharyngeal carcinoma","route":"/cancers/nasopharyngeal/"},{"id":"neuroendocrine","kind":"cancer","name":"Neuroendocrine tumours","route":"/cancers/neuroendocrine/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"pathway":[{"id":"hepatocellular-carcinoma-signalling","kind":"pathway","name":"Hepatocellular carcinoma (KEGG map)","route":"/pathways/hepatocellular-carcinoma-signalling/"},{"id":"keap1-nrf2","kind":"pathway","name":"KEAP1-NRF2 antioxidant pathway","route":"/pathways/keap1-nrf2/"}],"term":[{"id":"stk11-keap1","kind":"term","name":"STK11 / KEAP1 co-mutations","route":"/terms/stk11-keap1/"}],"trial":[{"id":"nct05276726","kind":"trial","name":"A Study of JAB-21822 in Advanced or Metastatic NSCLC With KRAS p.G12C and STK11 Co-mutation and Wild-type KEAP1","route":"/trials/nct05276726/"},{"id":"nct06008093","kind":"trial","name":"A Study to Investigate the Efficacy of Durvalumab Plus Tremelimumab in Combination With Chemotherapy Compared With Pembrolizumab in Combination With Chemotherapy in Metastatic NSCLC Patients With Non-squamous Histology Who Have Mutations and/or Co-mutations in STK11, KEAP1, or KRAS","route":"/trials/nct06008093/"}],"paper":[{"id":"paper-keynote-042-tmb-mutations-ann-oncol-2023","kind":"paper","name":"Associations of tissue tumour mutational burden and mutational status with clinical outcomes in KEYNOTE-042","route":"/key-papers/paper-keynote-042-tmb-mutations-ann-oncol-2023/"},{"id":"paper-keynote-189-407-tmb-jtocrr-2023","kind":"paper","name":"Associations of tissue tumour mutational burden and mutational status with clinical outcomes with pembrolizumab plus chemotherapy versus chemotherapy for metastatic non-small-cell lung cancer","route":"/key-papers/paper-keynote-189-407-tmb-jtocrr-2023/"},{"id":"paper-skoulidis-kras-co-mutation-subsets-cancer-discov-2015","kind":"paper","name":"Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities","route":"/key-papers/paper-skoulidis-kras-co-mutation-subsets-cancer-discov-2015/"},{"id":"paper-tcga-lung-squamous-nature-2012","kind":"paper","name":"Comprehensive genomic characterization of squamous cell lung cancers","route":"/key-papers/paper-tcga-lung-squamous-nature-2012/"},{"id":"paper-tcga-lung-adenocarcinoma-nature-2014","kind":"paper","name":"Comprehensive molecular profiling of lung adenocarcinoma","route":"/key-papers/paper-tcga-lung-adenocarcinoma-nature-2014/"},{"id":"paper-ricciuti-stk11-keap1-kras-immunotherapy-jto-2022","kind":"paper","name":"Diminished efficacy of programmed death-(ligand)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status","route":"/key-papers/paper-ricciuti-stk11-keap1-kras-immunotherapy-jto-2022/"},{"id":"paper-arbour-kras-co-mutation-outcomes-ccr-2018","kind":"paper","name":"Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer","route":"/key-papers/paper-arbour-kras-co-mutation-outcomes-ccr-2018/"},{"id":"paper-chen-east-asian-lung-adenocarcinoma-nat-genet-2020","kind":"paper","name":"Genomic landscape of lung adenocarcinoma in East Asians","route":"/key-papers/paper-chen-east-asian-lung-adenocarcinoma-nat-genet-2020/"},{"id":"paper-pandey-gallbladder-elf3-nat-commun-2020","kind":"paper","name":"Integrated genomic analysis reveals mutated ELF3 as a potential gallbladder cancer vaccine candidate","route":"/key-papers/paper-pandey-gallbladder-elf3-nat-commun-2020/"},{"id":"paper-jordan-prospective-lung-adenocarcinoma-msk-cancer-discov-2017","kind":"paper","name":"Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies","route":"/key-papers/paper-jordan-prospective-lung-adenocarcinoma-msk-cancer-discov-2017/"},{"id":"paper-kras-nsclc-cancer-discov-2018","kind":"paper","name":"STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS -Mutant Lung Adenocarcinoma","route":"/key-papers/paper-kras-nsclc-cancer-discov-2018/"},{"id":"paper-schoenfeld-smarca4-alterations-lung-ccr-2020","kind":"paper","name":"The genomic landscape of SMARCA4 alterations and associations with outcomes in patients with lung cancer","route":"/key-papers/paper-schoenfeld-smarca4-alterations-lung-ccr-2020/"}]}}