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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.
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.
CIViC 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.
In plain words · 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.
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.
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.
No product in this corpus aims at KEAP1 yet. Because the protein is lost rather than overactive, drugs either restore its function or exploit the weakness its loss leaves (synthetic lethality).
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.)
Sources: UniProt Q14145; CIViC gene KEAP1; IntOGen KEAP1; Human Protein Atlas KEAP1 tissue; Open Targets ENSG00000079999 associations
First described 1995. 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". Source.
Sources: HGNC HGNC:23177 (approved symbol, name, aliases, locus and cross-references (hgnc_complete_set.txt)); UniProt Q14145 (protein name, function text, keywords and locations (REST API)); CIViC gene KEAP1 (6 evidence items, 0 assertions, 2 variants; diseases: Lung Non-small Cell Carcinoma (GraphQL API, CC0)); Open Targets ENSG00000079999 (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)); IntOGen KEAP1 (driver in 14 cohorts (Act 7, LoF 7); Compendium_Cancer_Genes.tsv release 20240920, CC0 1.0)
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).
RNA: tissue enhanced (skeletal muscle 171 nTPM), detected in all normal tissues.
Medium: Appendix, Bone marrow, Breast, Bronchus, Caudate, Colon, Duodenum, Endometrium.
Medium only: breast cancer, carcinoid, cervical cancer, head and neck cancer.
HPA KEAP1 tissue · HPA KEAP1 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 |
|---|---|---|---|---|
| Non-small-cell lung cancer | 11-18% | Inactivating mutation | 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). | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
It is the positive half of the tumour mutational burden story and it applies only to single-agent immunotherapy, which is the setting fewest patients are treated in.
This is the result that ended tumour mutational burden as a practical selector in lung cancer: in the regimen most patients receive, it selects nobody, and neither do the co-mutations most often quoted as reasons to withhold immunotherapy.
It corrected a widely repeated simplification. An STK11 or KEAP1 mutation is not by itself a reason to expect immunotherapy to fail; it is a reason to expect it in a KRAS-mutant tumour, which is how the result should be read on a report.
It shows that the driver frequencies quoted in Western guidelines are population statistics rather than facts about the disease, which matters for how many patients anywhere are expected to benefit from a given medicine.
A three-continent cohort from high-incidence countries, and the origin of the idea that a shared frameshift (ELF3) could be a vaccine target in a cancer with few targets. CTNNB1 and STK11 from this list recur in the MSK data.
It turned a frequently reported variant into an interpretable one: the class decides whether the stain will be negative, how poor the prognosis is, and whether immunotherapy is more rather than less likely to help.
It separated the prognostic co-mutation, KEAP1, from the predictive one, STK11, in a disease where the two are often quoted together, and it is the reason KEAP1 status is worth reading off a report even though no treatment depends on it.
One of the most cited trial reports Europe PMC returns for KRAS in Non-small-cell lung cancer, so it is a natural first reading for anyone weighing the idea it is linked from. The record was linked automatically by title and abstract; read the abstract above and the paper itself before relying on any figure.
Query for this target: (TITLE:"KEAP1" OR ABSTRACT:"KEAP1" OR TITLE:"kelch like ECH associated protein 1" OR ABSTRACT:"kelch like ECH associated protein 1" OR TITLE:"Kelch-like ECH-associated protein 1" OR ABSTRACT:"Kelch-like ECH-associated protein 1" OR TITLE:"KIAA0132" OR ABSTRACT:"KIAA0132" OR TITLE:"MGC10630" OR ABSTRACT:"MGC10630" OR TITLE:"MGC1114" OR ABSTRACT:"MGC1114") 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 KEAP1, not a curated reading list.
Shares A Study of JAB-21822 in Advanced or Metastatic NSCLC With KRAS p.G12C and STK11 Co-mutation and Wild-type KEAP1, Integrated genomic analysis reveals mutated ELF3 as a potential gallbladder cancer vaccine candidate, 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, STK11 / KEAP1 co-mutations.
Shares Integrated genomic analysis reveals mutated ELF3 as a potential gallbladder cancer vaccine candidate, Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer, KEAP1-NRF2 antioxidant pathway, Comprehensive genomic characterization of squamous cell lung cancers.
Shares The genomic landscape of SMARCA4 alterations and associations with outcomes in patients with lung cancer, Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer, Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies, Lung cancer (all types).
Shares Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities, Comprehensive molecular profiling of lung adenocarcinoma, IntOGen, Lung cancer (all types).
Shares The genomic landscape of SMARCA4 alterations and associations with outcomes in patients with lung cancer, Neuroendocrine tumours, CIViC, IntOGen.
Shares Comprehensive molecular profiling of lung adenocarcinoma, Biliary tract cancer (cholangiocarcinoma), IntOGen, Lung cancer (all types).
Shares The genomic landscape of SMARCA4 alterations and associations with outcomes in patients with lung cancer, Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer, STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS -Mutant Lung Adenocarcinoma, Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities.
Shares Integrated genomic analysis reveals mutated ELF3 as a potential gallbladder cancer vaccine candidate, Hepatocellular carcinoma (KEGG map), Hepatocellular carcinoma, CIViC.