Deciphering the Role of Acetate in Metabolic Adaptation and Drug Resistance in Non-Small Cell Lung Cancer

Resistance to targeted therapies remains a major challenge in EGFR-mutant non-small cell lung cancer (NSCLC). Here, we describe a novel metabolic adaptation in osimertinib-resistant cells characterized by elevated acetate levels and activation of an unconventional pyruvate/acetaldehyde/acetate (PAA) shunt. Integrated transcriptomic, exometabolomic, and functional analyses reveal suppression of canonical metabolic pathways and upregulation of ALDH2 and ALDH7A1, which mediate the NADP+ dependent oxidation of acetaldehyde to acetate, generating NADPH. This shift supports reducing power essential for biosynthesis and redox balance under conditions of oxidative pentose phosphate inhibition. These metabolic changes promote endurance in resistant cells and rewire the interplay between glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle, offering a de novo bypass for anaplerosis and bioenergetics. Systematic metabolite profiling revealed distinct transcriptomic and metabolic signatures distinguishing resistant from parental cells. Together, these findings depict a unique, resistance-driven adaptive metabolic shift, and uncover potential therapeutic vulnerabilities in osimertinib-resistant NSCLC.