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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.
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.
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.
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 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 pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
It is the origin of the idea, now central to lung oncology, that the co-mutation and not the driver decides how a KRAS-mutant tumour behaves and whether immunotherapy will work.
It is the reference table the field still argues against, and it made two practical points that outlived it: a tumour with no driver on a standard panel usually has one that the panel did not look for, and pathway activity measured on protein does not follow from the mutation list.
It explained why squamous lung cancer has no equivalent of an EGFR inhibitor: its commonest alterations are a transcription factor amplicon, a tumour suppressor deletion and an antioxidant switch, none of which is a drug target in the way a mutant kinase is.
Shares Cancer metabolism, RAS / RAF / MEK / ERK (MAPK), KRAS and the tag mechanism.
Shares Cancer metabolism, MD Anderson Cancer Center, Non-small-cell lung cancer and the tag mechanism.
Shares Memorial Sloan Kettering Cancer Center, RAS / RAF / MEK / ERK (MAPK), KRAS and the tag mechanism.
Shares Glutamine addiction, Cancer metabolism, RAS / RAF / MEK / ERK (MAPK), KRAS and the tag mechanism.
Shares Memorial Sloan Kettering Cancer Center, RAS / RAF / MEK / ERK (MAPK) and the tag mechanism.
Shares MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center and the tag mechanism.
Shares Comprehensive genomic characterization of squamous cell lung cancers, Memorial Sloan Kettering Cancer Center, Non-small-cell lung cancer and the tag mechanism.
Shares Drug efflux pumps (ABC transporters), Memorial Sloan Kettering Cancer Center and the tag mechanism.