AHSA1-HSP90AA1 complex stabilized IFI6 and TGFB1 promotes mitochondrial stability and EMT in EGFR-mutated lung adenocarcinoma under Osimertinib pressure

Tyrosine kinase inhibitors (TKIs) have substantially improved the management of lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations, yet resistance to these therapies, such as Osimertinib, inevitably develops. We found that the overexpression of IFI6 under the influence of the AHSA1-HSP90AA1 complex significantly enhances Osimertinib resistance in EGFR-mutated lung adenocarcinoma cells. This effect is achieved by stabilizing mitochondrial function, reducing apoptosis, and promoting cell survival pathways via increased Akt phosphorylation. Additionally, we revealed that TGFB1 further promotes epithelial-mesenchymal transition (EMT) and enhances the invasive and migratory capabilities of these cells, thereby intensifying resistance. Regarding mechanisms, the AHSA1-HSP90AA1 complex stabilizes IFI6 and TGFB1 to enhance cell survival and Osimertinib resistance in EGFR mutant lung adenocarcinoma. IFI6 not only aids in cellular survival under drug stress but also promotes aggressive tumor phenotypes, suggesting its viability as a novel biomarker and therapeutic target for overcoming TKI resistance.