# KEAP1-NRF2 antioxidant pathway

Source: https://onco.cc/pathways/keap1-nrf2/  
OnCo record `keap1-nrf2` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Pathway
- Last checked: 2026-09-08
- Tags: mechanism
- 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.
- 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

## Notes

- Leading programmes: Papagiannakopoulos (NYU) on KEAP1 in lung cancer; DeNicola (Moffitt); Skoulidis and Heymach (MD Anderson) on STK11/KEAP1 and IO.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/NFE2L2
- Romero et al., Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis (Nature Medicine 2017): https://doi.org/10.1038/nm.4407

## Connected records

- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- targets: [KEAP1](https://onco.cc/targets/keap1/), [KRAS](https://onco.cc/targets/kras/), [NFE2L2](https://onco.cc/targets/nfe2l2/), [NQO1](https://onco.cc/targets/nqo1/), [STK11](https://onco.cc/targets/stk11/)
- institutions: [MD Anderson Cancer Center](https://onco.cc/institutions/md-anderson/), [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/)
- pathways: [Cancer metabolism](https://onco.cc/pathways/cancer-metabolism/), [Drug efflux pumps (ABC transporters)](https://onco.cc/pathways/drug-efflux-pumps/), [Ferroptosis & regulated cell death](https://onco.cc/pathways/ferroptosis-cell-death/), [Glutamine addiction](https://onco.cc/pathways/glutamine-metabolism/), [Hepatocellular carcinoma (KEGG map)](https://onco.cc/pathways/hepatocellular-carcinoma-signalling/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- terms: [Drug efflux pumps (ABC transporters)](https://onco.cc/terms/efflux-pump/), [Hallmark: reprogramming cellular metabolism](https://onco.cc/terms/deregulating-cellular-energetics/)
- key papers: [Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities](https://onco.cc/key-papers/paper-skoulidis-kras-co-mutation-subsets-cancer-discov-2015/), [Comprehensive genomic characterization of squamous cell lung cancers](https://onco.cc/key-papers/paper-tcga-lung-squamous-nature-2012/), [Comprehensive molecular profiling of lung adenocarcinoma](https://onco.cc/key-papers/paper-tcga-lung-adenocarcinoma-nature-2014/), [Diminished efficacy of programmed death-(ligand)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status](https://onco.cc/key-papers/paper-ricciuti-stk11-keap1-kras-immunotherapy-jto-2022/), [Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer](https://onco.cc/key-papers/paper-arbour-kras-co-mutation-outcomes-ccr-2018/), [Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis](https://onco.cc/key-papers/paper-romero-nat-med/)
- biomarkers: [STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma](https://onco.cc/biomarkers/stk11-keap1-loss/)
- ideas: [Map metabolic dependencies in the patient, not the dish](https://onco.cc/ideas/idea-metabolic-vulnerability-mapping/)

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