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MicroRNA-130a-3p regulates osimertinib resistance by targeting runt-related transcription factor 3 in lung

Takuya Shintani1, Yu-Ting Shun2, Yuji Toyozumi3

  • 1Department of Pharmacy, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka, 565-0871, Japan. shintani@hosp.med.osaka-u.ac.jp.

Scientific Reports
|October 18, 2024
PubMed

Insights

Extracellular vesicle microRNAs (EV-miRNAs) drive osimertinib resistance in lung cancer. Inhibiting miR-130a-3p may overcome resistance and serve as a predictive biomarker for improved patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Lung adenocarcinoma treatment faces challenges due to resistance to epidermal growth factor receptor tyrosine kinase inhibitors like osimertinib.
  • Extracellular vesicle (EV)-derived microRNAs (EV-miRNAs) are implicated in drug resistance and hold potential as diagnostic and therapeutic targets.

Purpose of the Study:

  • To identify EV-miRNAs associated with osimertinib resistance in lung adenocarcinoma.
  • To investigate the clinical relevance of identified EV-miRNAs as biomarkers for osimertinib resistance.

Main Methods:

  • Characterization of EVs from osimertinib-resistant (PC9OR, H1975OR) and sensitive (PC9, H1975) lung adenocarcinoma cell lines.
  • Microarray analysis to identify differentially expressed EV-miRNAs.
  • In vitro functional assays involving EV and miRNA transfection/inhibition.
  • Bioinformatics analysis to predict miRNA targets.
  • Correlation analysis between serum miRNA levels and patient progression-free survival.

Main Results:

  • Osimertinib-resistant cells exhibited increased EV release, and their EVs promoted osimertinib resistance in sensitive cells.
  • miR-130a-3p was significantly upregulated in EVs from resistant cell lines and promoted osimertinib resistance by targeting runt-related transcription factor 3.
  • Inhibition of miR-130a-3p reversed osimertinib resistance in resistant cells.
  • Lower baseline serum miR-130a-3p levels correlated with longer progression-free survival in patients.

Conclusions:

  • miR-130a-3p is a key mediator of osimertinib resistance in lung adenocarcinoma, acting via the miR-130a-3p/runt-related transcription factor 3 axis.
  • miR-130a-3p represents a potential therapeutic target to overcome osimertinib resistance.
  • Serum miR-130a-3p levels may serve as a predictive biomarker for osimertinib treatment response in lung adenocarcinoma patients.
Keywords:
Extracellular vesiclesLung adenocarcinomaMicroRNA-130a-3pOsimertinib resistanceRunt-related transcription factor 3

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