Abstract
Non-small cell lung cancer (NSCLC) remains a significant global health burden, accounting for the majority of lung cancer–related deaths. Despite the development of targeted therapies that improve outcomes for subsets of patients with defined oncogenic drivers, such as mutations in EGFR and KRAS, the emergence of resistance remains a major clinical challenge. This is often due to the survival of small subpopulations of cancer cells, called drug-tolerant persister (DTP) cells that can reinitiate tumour growth. Therefore, new therapeutic strategies that can complement existing targeted treatments and delay or prevent resistance are urgently needed.
MicroRNAs (miRNAs) have emerged as promising therapeutic tools due to their ability to modulate entire gene networks involved in cancer progression. The miR-15/107 family, in particular, is known for its tumour-suppressive properties and is frequently downregulated in NSCLC. A recent study by Reid, G. et al. showed that a synthetic consensus miRNA mimic based on this family could effectively suppress tumour cell proliferation in mesothelioma and NSCLC models. However, the utility of this construct in combination with targeted therapies in NSCLC remains largely unexplored. This project aimed to evaluate the therapeutic potential of a consensus miR-15/107 mimic (conmiR-15/107) in NSCLC models, particularly in the context of targeted therapy. The construct was tested across five NSCLC cell lines with varying oncogenic drivers. Dose– response assays demonstrated that conmiR-15/107 induced robust, dose-dependent inhibition of cell viability. Combination assays revealed that the construct sensitised EGFR-mutant PC9 cells to EGFR inhibitors (osimertinib and gefitinib) as well as the MEK inhibitor trametinib in a synergistic manner. In KRAS-mutant A549 cells, sensitisation to osimertinib, erlotinib, and the MEK inhibitor trametinib was observed, though the effects were additive. KRASG12C-mutant H358 cells showed enhanced sensitivity to KRAS inhibitors sotorasib and adagrasib, with evidence of synergy.
Long-term proliferation assays indicated that conmiR-15/107 delayed the emergence of DTP cells in both osimertinib- and sotorasib-treated cultures, suggesting its potential to reduce resistance development. Molecular analyses confirmed the downregulation of several oncogenic targets at the mRNA level, including MEK1, BCL2, BRCA1, and FGFR1 in PC9 cells, with MEK1 also suppressed at the protein level in PC9 and H358 cells. These findings support a multi-target mechanism of action underlying the construct's phenotypic effects. Together, this study provides strong preclinical evidence that conmiR-15/107 enhances the efficacy of targeted therapies in NSCLC models, delays the development of resistance, and acts through the suppression of multiple cancer-relevant targets. These results warrant further investigation into conmiR-15/107 as a potential therapeutic adjunct in NSCLC.