Abstract Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, show robust clinical efficacy in EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), yet acquired resistance remains inevitable. Here, we demonstrate that osimertinib and other EGFR-TKIs suppress PPARGC1B expression and its regulated mitochondrial biogenesis in EGFRm NSCLC cells through a previously unrecognized FOSL1/AP-1-mediated transactivation mechanism. Upon acquisition of osimertinib resistance, PPARGC1B expression and its encoded protein PGC1β rebound and become refractory to osimertinib-mediated suppression. Enforced overexpression of PPARGC1B confers resistance to osimertinib in sensitive EGFRm NSCLC cells, whereas PPARGC1B knockdown restores drug sensitivity in resistant cells. Moreover, combining osimertinib with the mitochondria-targeting agent CPI-613 synergistically suppresses mitochondrial biogenesis, induces apoptosis, and inhibits the growth of osimertinib-resistant cells and tumors. Collectively, these findings identify PGC1β-dependent mitochondrial biogenesis as a critical determinant of therapeutic response to osimertinib and suggest co-targeting mitochondrial metabolism as a potential strategy to overcome acquired resistance in EGFRm NSCLC.
Chen et al. (2026) studied this question.