Keap1 Deficiency Drives Glucose Dependency and Sensitizes Lung Cancer Cells and Tumors to Glut Inhibition

Abstract

Metabolic reprogramming in cancer cells can create metabolic liabilities which could be exploited therapeutically. Tumor suppressor KEAP1 is frequently mutated in lung cancer, and KEAP1-mutant lung cancers are refractory to most current therapies. Here we show that KEAP1 deficiency promotes glucose dependency in lung cancer cells, and KEAP1-mutant or -deficient lung cancer cells are more vulnerable to glucose deprivation than KEAP1-proficient lung cancer cells. Mechanistically, KEAP1 inactivation in lung cancer cells leads to constitutive activation of NRF2 transcription factor and aberrant expression of NRF2 target cystine transporter SLC7A11; under glucose limiting conditions, high cystine uptake in KEAP1-inactivated lung cancer cells results in toxic buildup of intracellular disulfide molecules, NADPH depletion, and subsequent cell death, which can be rescued by either genetic ablation of the NRF2-SLC7A11 signaling axis or treatments that prevent disulfide accumulation. Finally, we show that KEAP1-inactivated lung cancer cells or xenograft tumors are sensitive to glucose transporter (GLUT) inhibitor KL-11743. Together, our results reveal that KEAP1 deficiency induces glucose dependency in lung cancercells and uncover a metabolic liability that can be therapeutically targeted in KEAP1-mutant lung cancer.