{"entity":{"id":"keap1-nrf2","kind":"pathway","name":"KEAP1-NRF2 antioxidant pathway","aka":[],"tldr":"KEAP1-NRF2 is the cell's antioxidant defence switch. Lung cancers often break the off-switch (KEAP1), leaving NRF2 permanently on, which detoxifies chemotherapy and radiation and makes these tumours resistant to almost everything.","summary":"KEAP1 targets NRF2 (NFE2L2) for degradation; oxidative stress or KEAP1 mutation (~20% of lung adenocarcinoma, often with KRAS or STK11) stabilises NRF2, inducing glutathione synthesis, drug efflux, and NADPH production. KEAP1/STK11-mutant NSCLC responds poorly to chemotherapy and immunotherapy. Vulnerabilities: glutaminase dependence (telaglenastat, KEAPSAKE trial negative), NRF2-activated prodrugs (TRC102?), and CDK4/6 dependence; NRF2 also drives ferroptosis resistance.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/NFE2L2","links":[{"label":"Romero et al., Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis (Nature Medicine 2017)","url":"https://doi.org/10.1038/nm.4407"}],"tags":["mechanism"],"related":[],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":["kras"],"drugs":[],"companies":[],"institutions":["mskcc","md-anderson"],"pathways":["ferroptosis-cell-death","cancer-metabolism","ras-mapk"],"terms":["efflux-pump"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-romero-nat-med"],"journals":[],"dependsOn":[],"notes":["Leading programmes: Papagiannakopoulos (NYU) on KEAP1 in lung cancer; DeNicola (Moffitt); Skoulidis and Heymach (MD Anderson) on STK11/KEAP1 and IO."],"analogy":"KEAP1-NRF2 is a smoke detector wired to a sprinkler system. Cancers jam the detector on, so the sprinklers run constantly and wash away every poison you throw at them.","nodes":[{"id":"ros","label":"Oxidative stress","x":12,"y":40},{"id":"keap","label":"KEAP1 (mutated)","x":38,"y":40},{"id":"nrf2","label":"NRF2","x":62,"y":40},{"id":"are","label":"ARE genes: GSH, NQO1, efflux","x":86,"y":40},{"id":"res","label":"Chemo/RT/ferroptosis resistance","x":86,"y":80},{"id":"stk11","label":"STK11/LKB1 loss (co-mutation)","x":38,"y":80}],"edges":[{"from":"ros","to":"keap","type":"inhibits"},{"from":"keap","to":"nrf2","type":"inhibits"},{"from":"nrf2","to":"are","type":"activates"},{"from":"are","to":"res","type":"activates"},{"from":"stk11","to":"res","type":"activates"}],"interventions":["Glutaminase inhibition (negative in KEAPSAKE)","NRF2-activated prodrugs and NRF2 inhibitors (preclinical)","Biomarker: KEAP1/STK11 status predicts poor IO benefit in NSCLC","CDK4/6 and mTOR combinations under study"]},"route":"/pathways/keap1-nrf2/","neighbours":{"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"target":[{"id":"keap1","kind":"target","name":"KEAP1","route":"/targets/keap1/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"nfe2l2","kind":"target","name":"NFE2L2","route":"/targets/nfe2l2/"},{"id":"nqo1","kind":"target","name":"NQO1","route":"/targets/nqo1/"},{"id":"stk11","kind":"target","name":"STK11","route":"/targets/stk11/"}],"institution":[{"id":"md-anderson","kind":"institution","name":"MD Anderson Cancer Center","route":"/institutions/md-anderson/"},{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"}],"pathway":[{"id":"cancer-metabolism","kind":"pathway","name":"Cancer metabolism","route":"/pathways/cancer-metabolism/"},{"id":"drug-efflux-pumps","kind":"pathway","name":"Drug efflux pumps (ABC transporters)","route":"/pathways/drug-efflux-pumps/"},{"id":"ferroptosis-cell-death","kind":"pathway","name":"Ferroptosis & regulated cell death","route":"/pathways/ferroptosis-cell-death/"},{"id":"glutamine-metabolism","kind":"pathway","name":"Glutamine addiction","route":"/pathways/glutamine-metabolism/"},{"id":"hepatocellular-carcinoma-signalling","kind":"pathway","name":"Hepatocellular carcinoma (KEGG map)","route":"/pathways/hepatocellular-carcinoma-signalling/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"term":[{"id":"efflux-pump","kind":"term","name":"Drug efflux pumps (ABC transporters)","route":"/terms/efflux-pump/"},{"id":"deregulating-cellular-energetics","kind":"term","name":"Hallmark: reprogramming cellular metabolism","route":"/terms/deregulating-cellular-energetics/"}],"paper":[{"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-romero-nat-med","kind":"paper","name":"Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis","route":"/key-papers/paper-romero-nat-med/"}],"biomarker":[{"id":"stk11-keap1-loss","kind":"biomarker","name":"STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma","route":"/biomarkers/stk11-keap1-loss/"}],"idea":[{"id":"idea-metabolic-vulnerability-mapping","kind":"idea","name":"Map metabolic dependencies in the patient, not the dish","route":"/ideas/idea-metabolic-vulnerability-mapping/"}]}}