REGULATION OF AMPK ACTIVATION AND ITS ROLE IN CELL DEATH INDUCED BY GLUCOSE STARVATION IN LKB1-MUTANT HUMAN LUNG CANCER CELLS

Abstract

Clinically approved EGFR inhibitors are not available for the non-small cell lung cancer (NSCLC) patients without EGFR mutation. Our study found that EGFR and LKB1 mutations are mutually exclusive in NSCLC. LKB1 and its most important substrate AMPK facilitate cell survival under stress conditions. LKB1-mutant NSCLC cells are thus resistant to EGFR inhibitor erlotinib, but highly sensitive to cell death induced by glucose starvation and the glucose transporter SGLT2 inhibitor canagliflozin. Mechanistically, AMPK activation is impaired in LKB1-mutant NSCLC cells, and glucose starvation increases ROS generation, leading to cell death. Canagliflozin mimics the effect of glucose starvation by inhibiting glucose uptake via SGLT2 in vitro. More importantly, canagliflozin reduces tumor growth formed by LKB1-mutant NSCLC cells in a mice xenograft model. In summary, our study demonstrates that LKB1 mutation is a potential therapeutic target for NSCLC treatment using SGLT2 inhibitors.