Long non-coding RNAs in lung cancer: implications for lineage plasticity-mediated TKI resistance

Abstract

The efficacy of targeted therapy in non-small-cell lung cancer (NSCLC) has been impeded by various mechanisms of resistance. Besides the mutations in targeted oncogenes, reversible lineage plasticity has recently considered to play a role in the development of tyrosine kinase inhibitors (TKI) resistance in NSCLC. Lineage plasticity enables cells to transfer from one committed developmental pathway to another, and has been a trigger of tumor adaptation to adverse microenvironment conditions including exposure to various therapies. More importantly, besides somatic mutation, lineage plasticity has also been proposed as another source of intratumoural heterogeneity. Lineage plasticity can drive NSCLC cells to a new cell identity which no longer depends on the drug-targeted pathway. Histological transformation and epithelial–mesenchymal transition are two well-known pathways of lineage plasticity-mediated TKI resistance in NSCLC. In the last decade, increased re-biopsy practice upon disease recurrence has increased the recognition of lineage plasticity induced resistance in NSCLC and has improved our understanding of the underlying biology. Long non-coding RNAs (lncRNAs), the dark matter of the genome, are capable of regulating variant malignant processes of NSCLC like the invisible hands. Recent evidence suggests that lncRNAs are involved in TKI resistance in NSCLC, particularly in lineage plasticity-mediated resistance. In this review, we summarize the mechanisms of lncRNAs in regulating lineage plasticity and TKI resistance in NSCLC. We also discuss how understanding these themes can alter therapeutic strategies, including combination therapy approaches to overcome TKI resistance.

Clinicopathologic Features and Molecular Biomarkers as Predictors of Epidermal Growth Factor Receptor Gene Mutation in Non-Small Cell Lung Cancer Patients

“…Long non-coding RNAs (lncRNAs) are involved in gene expression, mRNA splicing, and protein subcellular localization through cis and trans mechanisms, and regulate variant malignant processes of NSCLC by epigenetic modification [ 91 , 92 ]. EGFR-TKI resistance, where lncRNAs are involved, is one of the main challenges in the targeted therapy of EGFR-mutant NSCLC.…”

m6A methyltransferase METTL3-induced lncRNA SNHG17 promotes lung adenocarcinoma gefitinib resistance by epigenetically repressing LATS2 expression

“…Abundant evidence suggests that lncRNAs can regulate drug resistance in human lung cancer cells through multiple mechanisms [32,33]. The role of lncRNA SNHG17 in lung cancer was first reported by Xu Tianwei et al in 2019.…”

Lineage Plasticity in Cancer: The Tale of a Skin-Walker

“…Loss of ARID1A expression in tumor cells and patients determines resistance to endocrine therapy by promoting a switch from ER-dependent luminal cells to ER-independent basal cells [ 183 ]. Besides epigenetic factors, long non-coding RNAs can also modulate cellular plasticity as shown in lung and prostate cancer [ 184 , 185 , 186 , 187 ]). Genetic and epigenetic modulators can crosstalk and promote cellular plasticity; for instance, in prostate cancer, TP53 and RB1 loss can cause upregulation of SOX2 and EZH2 [ 156 , 188 ] and consequently an epigenetically permissive state facilitating lineage plasticity.…”