Elevated expression of miR-494-3p is associated with resistance to osimertinib in EGFR T790M-positive non-small cell lung cancer

Publication Date: 30 May 2022

Kaźmierczak, D. et al. (2022) Elevated expression of miR-494-3p is associated with resistance to osimertinib in EGFR T790M-positive non-small cell lung cancer. Transl. Lung Cancer Res. 11(5), 722–734. DOI: 10.21037/tlcr-21-955

Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases in the US. The main types of NSCLC are adenocarcinomas, squamous-cell carcinomas and—less commonly—large-cell carcinomas. One of the most common targetable genetic aberrations in NSCLC is activating mutations in the epidermal growth factor receptor (EGFR) gene; in these cases, treatment with tyrosine kinase inhibitors (TKIs) has shown clinical benefit. In particular, the third-generation TKI osimertinib has proven superior in treatment of advanced-stage NSCLC with EGFR mutations.

A significant issue with TKI treatment is the eventual development of resistance, especially with first- and second-generation inhibitors. Earlier studies showed that inhibition of a specific microRNA (miRNA) could restore sensitivity to TKIs in NSCLC cells in vitro. The current study aimed to investigate the involvement of miRNAs in acquired resistance to osimertinib and to determine whether specific miRNAs could serve as markers for osimertinib resistance.

miRNA expression profiling in parental and osimertinib-refractory EGFR mutant NSCLC cell lines identified several miRNAs that were differentially expressed. Inhibitory screening revealed a specific miRNA (miR-494-3p) that partially conferred resistance to osimertinib in osimertinib-refractory cells. Using a pan-cancer array, the researchers identified 18 transcripts displaying >2-fold differential expression in osimertinib-resistant cells compared with parental cells; 10 of these transcripts were predicted mIR-494-3p targets in silico. Further, analysis of plasma samples from NSCLC patients with mutated EGFR receiving osimertinib treatment showed that miR-494-3p was significantly elevated in plasma sampled at disease progression, compared to plasma sampled at treatment baseline. The researchers conclude that miR-494-3p may serve as a potential biomarker to monitor NSCLC disease progression in patients treated with osimertinib. Further study will be required to determine the therapeutic potential of miR-494-3p in vivo.

Keywords: non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR), osimertinib, microRNA (miRNA); tyrosine kinase inhibitor (TKI)