Inhibition of PGC1b/mitochondrial biogenesis as a critical event in mediating therapeutic response of EGFR mutant NSCLC to third generation EGFR inhibitors

Third generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are used for the treatment of advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. However, despite robust clinical efficacy of these agents, the inevitable issue of acquired resistance needs to be urgently addressed. Here we reported PPARGC1B expression was downregulated, and its regulated mitochondrial biogenesis was inhibited by osimertinib as well other EGFR-TKIs in EGFR mutant (EGFRm) NSCLC cells through a previously unidentified FOSL1/AP-1-mediated transactivation of the PPARGC1B gene. Once cells or tumors became resistant to osimertinib, PGC1beta encoded by PPARGC1B showed rebound elevation and was resistant to downregulation by osimertinib. Enforced overexpression of PPARGC1B in osimertinib-sensitive EGFRm NSCLC cell lines conferred resistance to osimertinib, whereas knockdown of PPARGC1B in osimertinib-resistant cells restored sensitivity to osimertinib. Moreover, osimertinib combined with a mitochondria-targeting agent such as CPI-613 synergistically decreased cell survival with enhanced suppression of mitochondrial biogenesis and induction of apoptosis in osimertinib-resistant cells and effectively inhibited the growth of osimertinib-resistant tumors. Hence, it is apparent that the modulation of PGC1beta/mitochondrial biogenesis critically impacts the therapeutic outcomes of osimertinib in the treatment of EGFRm NSCLC. Our findings not only reveal a novel mechanism underlying osimertinib acquired resistance, but also suggest a potential therapeutic strategy for overcoming acquired resistance to osimertinib via co-targeting PGC1beta, particularly mitochondrial biogenesis.