What question did this study set out to answer?

The aim is to understand how inhibition of PGC1b and mitochondrial biogenesis affects treatment responses in EGFR mutant NSCLC.

April 5, 2026

Abstract 7033: Inhibition of PGC1b/mitochondrial biogenesis as a critical event in mediating therapeutic response of EGFR mutant NSCLC to third generation EGFR inhibitors.

Key Points

The aim is to understand how inhibition of PGC1b and mitochondrial biogenesis affects treatment responses in EGFR mutant NSCLC.
Assessment of PPARGC1B expression and its role in mitochondrial biogenesis in NSCLC cells.
Evaluation of osimertinib and other EGFR-TKIs effects on PPARGC1B expression.
Investigation of resistance mechanisms in EGFR mutant NSCLC cells through gene overexpression and knockdown studies.
Combination treatment with osimertinib and a mitochondria-targeting agent CPI-613.
Osimertinib reduced PPARGC1B expression and inhibited mitochondrial biogenesis.
Resistant cells showed increased PGC1β levels, which were not suppressed by osimertinib.
Enforced overexpression of PPARGC1B induced resistance, while knockdown restored sensitivity.
Combining osimertinib with CPI-613 enhanced apoptosis and decreased cell survival in resistant cells.

Abstract

Abstract 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, PGC1β 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 PGC1β/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 PGC1β, particularly mitochondrial biogenesis. Citation Format: Zhen Chen, Dongsheng Wang, Songqing Fan, Qiming Wang, Suresh S. Ramalingam, Shi-Yong Sun. Inhibition of PGC1b/mitochondrial biogenesis as a critical event in mediating therapeutic response of EGFR mutant NSCLC to third generation EGFR inhibitors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7033.

Perguntar à IA

Bookmark