MicroRNA Mimics Based on the miR-15/107 Consensus Sequence Sensitise NSCLC Cells to Targeted Therapy

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Non-small cell lung cancer (NSCLC) presents a significant challenge due to resistance to targeted therapies.
• Drug-tolerant persister (DTP) cells are crucial drivers of this resistance.
• MicroRNAs (miRNAs), specifically the miR-15/107 family, show potential in targeting multiple oncogenic pathways.

Purpose of the Study:

• To evaluate the efficacy of a synthetic consensus miRNA mimic, conmiR-15/107, in NSCLC models.
• To assess its potential to overcome resistance to targeted therapies.
• To investigate its mechanism of action against DTPs.

Main Methods:

• Dose-response assays were performed on NSCLC cell lines (PC9, H358, A549) and a normal cell line (BEAS-2B).
• Combinatorial studies involved conmiR-15/107 with EGFR inhibitors (osimertinib, gefitinib) and KRAS inhibitors (sotorasib, adagrasib).
• RT-qPCR was used to confirm target gene downregulation, and long-term assays assessed DTP survival and proliferation.

Main Results:

• ConmiR-15/107 demonstrated dose-dependent growth inhibition in EGFR-mutant and KRAS-mutant NSCLC cells.
• The mimic enhanced the efficacy of EGFR and KRAS inhibitors, reducing IC50 values.
• Downregulation of MEK1, BCL2, and BRCA1 was confirmed, and conmiR-15/107 reduced DTP survival and proliferation.

Conclusions:

• ConmiR-15/107 shows significant potential as an adjunct therapy for lung adenocarcinoma.
• It enhances the efficacy of targeted therapies and delays the development of resistance.
• The multi-target mechanism involving DTPs supports its clinical relevance.