MicroRNA-601 Enhances Osimertinib Sensitivity by Targeting Transient Receptor Potential Mucolipin 3 in Non-small Cell...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Acquired resistance to tyrosine kinase inhibitors (TKIs) like osimertinib is a significant challenge in non-small cell lung cancer (NSCLC) treatment.
• Lysosomal Ca2+ signaling, mediated by transient receptor potential mucolipin 3 (TRPML3), is implicated in TKI resistance through enhanced drug efflux.
• The role of microRNA-601 (miR-601) in regulating TRPML3 and its impact on osimertinib resistance in NSCLC requires investigation.

Purpose of the Study:

• To investigate the regulatory role of miR-601 in modulating TRPML3 expression.
• To determine the impact of miR-601 on osimertinib resistance in NSCLC cells.
• To explore the potential of restoring miR-601 as a therapeutic strategy.

Main Methods:

• Bioinformatic analysis (DIANA microT-CDS) to predict miR-601 targets.
• Luciferase reporter assays to confirm direct binding of miR-601 to TRPML3 3'-UTR.
• Functional assays in parental and osimertinib-resistant NSCLC cell lines (PC9, HCC827) evaluating miR-601 effects on TRPML3, apoptosis, cell cycle, and drug sensitivity.

Main Results:

• TRPML3 was identified as a direct target of miR-601.
• Osimertinib treatment decreased miR-601 levels in NSCLC cells, with lower basal expression in resistant cells.
• miR-601 overexpression reduced TRPML3, increased apoptosis, induced G0/G1 arrest, and restored osimertinib sensitivity, mimicking TRPML3 knockdown effects.

Conclusions:

• miR-601 negatively regulates TRPML3 expression in NSCLC cells.
• miR-601 modulates responses to TKIs, suggesting a role in overcoming osimertinib resistance.
• Restoring miR-601 levels offers a potential therapeutic approach targeting TRPML3-mediated lysosomal signaling in resistant NSCLC.