KEAP1–NRF2 antioxidant pathway
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.
In one picture
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.
Diagram
top- 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
top- Leading programmes: Papagiannakopoulos (NYU) on KEAP1 in lung cancer; DeNicola (Moffitt); Skoulidis and Heymach (MD Anderson) on STK11/KEAP1 and IO.
Pages like this
not linked directly; found by shared links- PathwayAutophagy
Shares Cancer metabolism, RAS / RAF / MEK / ERK (MAPK), KRAS and the tag mechanism.
- PathwayHippo–YAP/TAZ
Shares RAS / RAF / MEK / ERK (MAPK), Memorial Sloan Kettering Cancer Center, KRAS and the tag mechanism.
- PathwayMYC
Shares Glutamine addiction, Cancer metabolism, RAS / RAF / MEK / ERK (MAPK), KRAS and the tag mechanism.
- PathwayCancer cachexia
Shares Cancer metabolism, MD Anderson Cancer Center, Non-small-cell lung cancer and the tag mechanism.
- PathwaymRNA translation (eIF4F / mTOR)
Shares RAS / RAF / MEK / ERK (MAPK), Memorial Sloan Kettering Cancer Center and the tag mechanism.
- PathwayCancer neuroscience (nerve–tumour signalling)
Shares MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center and the tag mechanism.
- PathwayCancer stem cells & phenotypic plasticity
Shares Drug efflux pumps (ABC transporters), Memorial Sloan Kettering Cancer Center and the tag mechanism.
- PathwayCircadian control
Shares Memorial Sloan Kettering Cancer Center and the tag mechanism.