Inhibition of PGC1β-dependent mitochondrial biogenesis enhances EGFR-targeted therapy in lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) like osimertinib are effective against EGFR-mutant non-small cell lung cancer (NSCLC).
• Acquired resistance to EGFR-TKIs, including osimertinib, is a significant clinical challenge in NSCLC treatment.

Purpose of the Study:

• To investigate the molecular mechanisms underlying acquired resistance to osimertinib in EGFR-mutant NSCLC.
• To identify potential therapeutic strategies to overcome osimertinib resistance by targeting metabolic pathways.

Main Methods:

• Investigated the role of PPARGC1B and mitochondrial biogenesis in EGFR-TKI sensitivity and resistance.
• Utilized cell lines and xenograft models of EGFR-mutant NSCLC.
• Examined the effect of combining osimertinib with CPI-613, a mitochondria-targeting agent.

Main Results:

• Osimertinib and other EGFR-TKIs suppress PPARGC1B expression and mitochondrial biogenesis via a FOSL1/AP-1 pathway.
• PPARGC1B expression rebounds in osimertinib-resistant cells, conferring resistance.
• Overexpression of PPARGC1B induces osimertinib resistance, while knockdown restores sensitivity.
• Combination therapy with osimertinib and CPI-613 synergistically inhibits resistant cells and tumors by targeting mitochondrial metabolism.

Conclusions:

• PGC1β-dependent mitochondrial biogenesis is a key factor in osimertinib response and resistance in EGFR-mutant NSCLC.
• Co-targeting mitochondrial metabolism represents a promising strategy to overcome acquired resistance to osimertinib in NSCLC patients.