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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Liver kinase B1 (LKB1) is a tumor suppressor frequently mutated in non-small cell lung cancer (NSCLC).
• LKB1 mutations often co-occur with Kelch-like ECH-associated-protein 1 (KEAP1) mutations, impacting the NRF2 antioxidant response.
• LKB1-mutant NSCLC exhibits sensitivity to glucose starvation, suggesting metabolic targeting as a therapeutic avenue.

Purpose of the Study:

• To investigate the efficacy of targeting LKB1-KEAP1 co-mutant NSCLC.
• To evaluate the combined therapeutic potential of Canagliflozin (SGLT2 inhibitor) and Brusatol (NRF2 signaling inhibitor).
• To elucidate the underlying molecular mechanisms of the combined treatment.

Main Methods:

• Utilized Canagliflozin to mimic glucose starvation by inhibiting glucose uptake.
• Administered Brusatol to inhibit the NRF2 signaling pathway.
• Assessed anti-tumor effects of the combination therapy both in vitro and in vivo in LKB1-KEAP1 co-mutant NSCLC models.

Main Results:

• The combination of Canagliflozin and Brusatol demonstrated potent anti-tumor effects against LKB1-KEAP1 co-mutant NSCLC.
• Mechanistically, the combined treatment suppressed AKT activity and promoted AKT degradation.
• This led to significant apoptotic cell death in cancer cells.

Conclusions:

• Combined Canagliflozin and Brusatol treatment offers a promising therapeutic strategy for LKB1-KEAP1 co-mutant NSCLC.
• Targeting glucose metabolism and NRF2 signaling concurrently can overcome resistance mechanisms.
• Further clinical investigation is warranted to validate this therapeutic approach.