Abstract 1408 Mitochondrial Electron Transport Chain Inhibition Suppresses NRF2 Expression in NSCLC

Lung cancer is the leading cause of cancer-associated death in the US. Non-small cell lung cancer (NSCLC) accounts for 85% of all diagnosed lung cancer cases, which has a high frequency of mutations in the KEAP1/NRF2 circuit (15-34%). NRF2 is a stress-responsive transcription factor that regulates transcriptional programs in response to oxidative stress. KEAP1 directs NRF2 degradation, and accordingly, disruption of KEAP1 increases the abundance and activity of NRF2. KEAP1/NRF2 mutations result in constitutive NRF2 activation and chronic induction of a battery of NRF2 target genes, which confer profound resistance to chemo/radiation therapy.