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Updated: May 13, 2025

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
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AHSA1-HSP90AA1 complex stabilized IFI6 and TGFB1 promotes mitochondrial stability and EMT in EGFR-mutated lung

Ying Sui1,2, Ziyang Shen1,2, Rongtian Pan1,2

  • 1The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China.

Cell Death & Disease
|April 15, 2025
PubMed

Insights

Overcoming Osimertinib resistance in EGFR-mutated lung adenocarcinoma involves targeting the AHSA1-HSP90AA1 complex. This complex stabilizes IFI6 and TGFB1, promoting cell survival and resistance to tyrosine kinase inhibitors (TKIs).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Tyrosine kinase inhibitors (TKIs) like Osimertinib have improved outcomes for EGFR-mutated lung adenocarcinoma.
  • However, primary resistance to TKIs remains a significant clinical challenge.
  • Understanding resistance mechanisms is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate the role of the AHSA1-HSP90AA1 complex in Osimertinib resistance.
  • To elucidate the mechanisms by which IFI6 and TGFB1 contribute to drug resistance and tumor aggressiveness.
  • To identify potential therapeutic targets for overcoming TKI resistance in lung adenocarcinoma.

Main Methods:

  • Cell culture models of EGFR-mutated lung adenocarcinoma.
  • Western blotting to assess protein expression and phosphorylation (e.g., Akt).
  • Apoptosis assays and cell viability measurements.
  • Analysis of epithelial-mesenchymal transition (EMT) markers and cell migration assays.

Main Results:

  • Overexpression of IFI6, influenced by the AHSA1-HSP90AA1 complex, significantly enhances Osimertinib resistance.
  • IFI6 stabilizes mitochondrial function, reduces apoptosis, and promotes cell survival via Akt phosphorylation.
  • TGFB1 further promotes EMT, enhancing cell invasion and migration.
  • The AHSA1-HSP90AA1 complex stabilizes both IFI6 and TGFB1, contributing to resistance.

Conclusions:

  • The AHSA1-HSP90AA1-IFI6-TGFB1 axis plays a critical role in Osimertinib resistance in EGFR-mutated lung adenocarcinoma.
  • IFI6 promotes cell survival under drug stress and aggressive tumor phenotypes.
  • IFI6 is a potential biomarker and therapeutic target for overcoming primary TKI resistance.

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