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A multi-omics approach to identify the impact of miR-411ed on NSCLC TKI resistance
Daniel Del Valle Morales1, Giulia Romano1, Michela Saviana1
1Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
Abstract:
Tyrosine Kinase inhibitors (TKIs) are widely used as effective chemotherapeutic agents for treating patients with EGFR-mutated NSCLC. Unfortunately, after treatment, patients eventually develop resistance to TKI therapy. The most common resistance mechanism for the TKI Osimertinib is the overexpression of the MET Proto-Oncogene, Receptor Tyrosine Kinase (MET). We previously demonstrated that miR-411-5p A-to-I edited at position 5 (miR-411ed) can directly target MET in A549 and H1299 cells. MiR-411ed in combination with Osimertinib reduced cell proliferation in two TKI resistant EGFR-mutated cell lines: HCC827R and PC9R. MiR-411ed did not downregulate MET expression in HCC827R, suggesting an alternative mechanism for TKI response. In this study, we aim to identify the mechanism of miR-411ed TKI response using a multi-omics approach of RNAseq and protein mass spectrometry. In our cellular model, we identified miR-411ed affected genes independent of MET activity, resulting in 211 genes (RNAseq) and 36 proteins (proteomics). Pathway analysis identified an increase in interferon signaling for RNAseq and combined omics, and a decrease in ERK/MAPK signaling in proteomics. Using the IsoTar target prediction tool, we identified STAT3 as a key regulator and confirmed STAT3 protein downregulation upon transfection with miR-411ed. We further investigated the effect of miR-411ed in vivo, observing a reduction in tumor size with miR-411ed in combination with Osimertinib but not with miR-411ed or Osimertinib treatment alone, confirming the effectiveness of miR-411ed in TKI response.
Insights
This study reveals that miR-411ed overcomes TKI resistance in EGFR-mutated NSCLC by downregulating STAT3, not MET. Combining miR-411ed with Osimertinib effectively reduces tumor growth, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tyrosine Kinase Inhibitors (TKIs) are crucial for EGFR-mutated Non-Small Cell Lung Cancer (NSCLC).
- Acquired resistance to TKIs, often via MET overexpression, limits treatment efficacy.
- miR-411ed was previously shown to target MET and reduce proliferation in resistant cell lines.
Purpose of the Study:
- To elucidate the mechanism of TKI resistance reversal by miR-411ed.
- To investigate miR-411ed's effects independent of MET.
- To evaluate the therapeutic potential of miR-411ed in combination with Osimertinib.
Main Methods:
- Multi-omics approach: RNA sequencing (RNAseq) and protein mass spectrometry.
- IsoTar target prediction tool.
- In vitro cell line models (HCC827R, PC9R) and in vivo tumor xenografts.
Main Results:
- miR-411ed modulated 211 genes (RNAseq) and 36 proteins (proteomics) independently of MET.
- Interferon signaling was upregulated, while ERK/MAPK signaling decreased.
- STAT3 was identified as a key target, with its protein expression downregulated by miR-411ed.
- Combination therapy (miR-411ed + Osimertinib) significantly reduced tumor size in vivo.
Conclusions:
- miR-411ed overcomes TKI resistance through a MET-independent mechanism, primarily by downregulating STAT3.
- Combined miR-411ed and Osimertinib therapy demonstrates significant anti-tumor efficacy.
- This combination represents a promising strategy for overcoming TKI resistance in EGFR-mutated NSCLC.
