KEAP1 deficiency drives glucose dependency and sensitizes lung cancer cells and tumors to GLUT inhibition

Metabolic reprogramming in cancer cells can create metabolic liabilities. KEAP1-mutant lung cancer is refractory to most current therapies. Here we show that KEAP1 deficiency promotes glucose dependency in lung cancer cells, and KEAP1-mutant/deficient lung cancer cells are more vulnerable to glucose deprivation than their WT counterparts. Mechanistically, KEAP1 inactivation in lung cancer cells induces constitutive activation of NRF2 transcription factor and aberrant expression of NRF2 target cystine transporter SLC7A11; under glucose limitation, high cystine uptake in KEAP1-inactivated lung cancer cells stimulates toxic intracellular disulfide buildup, NADPH depletion, and cell death, which can be rescued by genetic ablation of NRF2-SLC7A11 axis or treatments inhibiting disulfide accumulation. Finally, we show that KEAP1-inactivated lung cancer cells or xenograft tumors are sensitive to glucose transporter inhibitor. Together, our results reveal that KEAP1 deficiency induces glucose dependency in lung cancer cells and uncover a therapeutically relevant metabolic liability.