MicroRNA-Mediated Drug Resistance in Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality worldwide, in part owing to the emergence of therapeutic resistance. MicroRNAs (miRNAs), a class of small non-coding RNAs, modulate key signalling pathways and cellular processes that underlie resistance to both chemotherapy and targeted agents. Dysregulated miRNA expression can alter drug uptake and efflux, enhance DNA repair, inhibit apoptosis and drive epithelial-to-mesenchymal transition (EMT). For example, overexpression of oncogenic miR-21 downregulates PTEN, activating AKT and ERK pathways and reducing sensitivity to tyrosine kinase inhibitors (TKIs), while loss of tumour-suppressive miRNAs such as the miR-17 family or miR-200 cluster contributes to cisplatin resistance via disinhibition of TGFβ and DNA damage-repair signalling. These molecules also serve as circulating biomarkers to predict response and prognosis, and their reversible nature makes them attractive targets for novel adjuvant strategies aimed at restoring drug sensitivity and improving clinical outcomes.

Research from Nature Portfolio

Studies have identified miR-488 as a critical modulator of cisplatin response in NSCLC by targeting the translation initiation factor eIF3a. Overexpression of miR-488 suppresses cell proliferation and migration through elevated p27 levels, yet paradoxically promotes cisplatin resistance by enhancing nucleotide excision repair (NER) via upregulation of replication protein A and XPC. Inhibition of miR-488 restores chemosensitivity, highlighting a dual role in tumour suppression and DNA repair regulation that may inform combination approaches to overcome resistance.

MicroRNA-Mediated Drug Resistance in Non-Small Cell Lung Cancer publication trend

The graph below shows the total number of articles in microrna-mediated drug resistance in non-small cell lung cancer across all publications each year (not limited to Nature Index journals).

Technical terms

MicroRNA (miRNA): small non-coding RNA molecules that regulate gene expression post-transcriptionally by binding to target mRNAs and inhibiting translation or promoting degradation.

Nucleotide excision repair (NER): a DNA repair pathway that removes bulky lesions such as cisplatin-induced adducts, restoring genomic integrity.

Tyrosine kinase inhibitor (TKI): a class of targeted therapy drugs that block the enzymatic activity of specific kinases such as EGFR to prevent oncogenic signalling.

Epithelial-to-mesenchymal transition (EMT): a cellular programme wherein epithelial cells acquire mesenchymal properties, associated with enhanced invasion, metastasis and drug resistance.

PI3K/AKT pathway: a central intracellular signalling cascade promoting cell survival and growth, often dysregulated in cancer and influenced by miRNA activity.

References

1. A literature review of microRNA and gene signaling pathways involved in the apoptosis pathway of lung cancer. Respiratory Research (2023).
2. Emerging role of non-coding RNAs in resistance to platinum-based anti-cancer agents in lung cancer. Frontiers in Pharmacology (2023).
3. miRNA 17 Family Regulates Cisplatin-Resistant and Metastasis by Targeting TGFbetaR2 in NSCLC. PLOS ONE (2014).
4. Alteration in Mir-21/PTEN Expression Modulates Gefitinib Resistance in Non-Small Cell Lung Cancer. PLOS ONE (2014).
5. MiR-488 inhibits proliferation and cisplatin sensibility in non-small-cell lung cancer (NSCLC) cells by activating the eIF3a-mediated NER signaling pathway. Scientific Reports (2017).
6. MicroRNA In Lung Cancer: Novel Biomarkers and Potential Tools for Treatment. Journal of Clinical Medicine (2016).