PKM2-deficiency induced fatty acid biosynthesis activation limits the response of non-small cell lung cancer to Osimertinib

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has revolutionized treatment for EGFR-mutant NSCLC, yet resistance significantly limits its clinical benefit to patients2. Here, using a genome-wide genetic screen, we discover that pyruvate kinase M2 (PKM2) is a novel regulator of Osimertinib resistance.

Loss of PKM2 triggers fatty acid biosynthesis activation in a glycolysis-independent manner. We have shown that PKM2 interacts with KDM1A in cytosol and nuclear translocation of KDM1A is increased in both PKM2-KO and Osimertinib-persister cells. Mechanistically, KDM1A demethylates H3K9me3 in the promoter region of the key lipid synthesis enzyme, fatty acid synthase (FASN), and cooperates with transcription factor AP-2 to activate FASN transcription, thereby conferring Osimertinib resistance.