Canagliflozin and Brusatol Synergize against LKB1-KEAP1 Co-Mutant NSCLC through AKT Suppression

Liver kinase B1 (LKB1, encoded by STK11) is an important tumour suppressor, with approximately 30% of non-small cell lung Cancer (NSCLC) patients harbouring LKB1 mutations. Our previous work showed that LKB1-mutant NSCLC cells are sensitive to glucose starvation, suggesting that suppression of glucose metabolism may serve as a potential therapeutic strategy for NSCLC patients with LKB1 mutation. In this study, we found LKB1 mutations frequently co-occur with mutations in Kelch-like ECH-associated-protein 1 (KEAP1), another key tumour suppressor regulating the NRF2-mediated antioxidant response. To target LKB1-KEAP1 co-mutant NSCLC, we utilized Canagliflozin, an FDA-approved sodium-glucose co-transporter 2 (SGLT2) inhibitor that mimics glucose starvation via inhibiting glucose uptake, in combination with Brusatol, an inhibitor of NRF2 signalling. Our results demonstrate that the combined treatment of Canagliflozin and Brusatol exerts potent anti-tumour effects in LKB1-KEAP1 co-mutant NSCLC cells both in vitro and in vivo. Mechanistically, the combination suppresses Akt activity and promotes Akt degradation, ultimately leading to apoptotic cell death. Taken together, these findings support the potential of combined Canagliflozin and Brusatol treatment as an effective therapeutic approach for LKB1-KEAP1 co-mutant NSCLCs.