Targeting GSTZ1 Sensitizes KRASG12C-Mutant Lung Cancer Cells by Overcoming Glutathione and Glycolysis Pathway...

KRAS mutations are prevalent in lung cancer, but KRASG12C inhibitors exhibit limited efficacy, partly due to metabolic adaptations, such as enhanced glutathione (GSH) metabolism and increased glycolysis. Glutathione S-transferase zeta 1 (GSTZ1) is a metabolic enzyme that regulates cell metabolism; however, its role in KRAS-driven lung cancer remains underexplored. We recently reported that targeting GSTZ1 significantly enhances the efficacy of FDA-approved KRASG12C inhibitors in non-small cell lung cancer (NSCLC) cells. Untargeted metabolomics now revealed significant alterations in GSH and glycolytic pathways, marked by lowered lactate levels and increased oxidized GSH following GSTZ1 ablation. Moreover, pharmacologic inhibition of GSH synthesis and glucose uptake mimicked the sensitizing effects of GSTZ1 targeting. These metabolic shifts were accompanied by increased AMPK phosphorylation and reduced AKT phosphorylation, two key mediators of the response to KRASG12C inhibition. Our data reveal GSTZ1-associated metabolic and signaling alterations that contribute to drug resistance and identify GSTZ1 as a potential complementary target to sensitize KRAS-mutant NSCLC to KRAS-directed treatments.

Targeting GSTZ1 sensitized KRASG12C-mutant NSCLC cells to KRASG12C inhibitors by disrupting glycolysis, GSH metabolism, and protein phosphorylation. GSTZ1 emerges as a mediator of drug resistance and a therapeutic target, supporting rational combination strategies that exploit metabolic vulnerabilities to enhance KRAS-targeted therapy efficacy and improve outcomes.