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.

Keywords: Lineage plasticity; Long non-coding RNAs; Non-small-cell lung cancer; Tyrosine kinase inhibitors.

Fig. 1

Lineage plasticity lead to TKI resistance in NSCLC. Upon targeted therapies, various molecular events can promote lineage plasticity, thereby driving intratumoural heterogeneity and drug resistance. RB1 and TP53 mutation or loss NSCLC cells are more likely to transdifferentiate into small cell tumors. Increased histone-modifying enzymes, such as enhancer of zeste homologue 2 (EZH2) and lineage-associated transcription factors, such as SOX family genes mediates the reprogramming of NSCLC into slow-cycling, drug-tolerant cell states. These slow-cycling, drug-tolerant cells generally present neuroendocrine differentiation and epithelial-to-mesenchymal transition (EMT). Alterations of key signaling pathways and crosstalk with the tumor microenvironment also control lineage plasticity. Collectively, the plasticity-permissive molecular environment under the pressure of targeted therapies trigger the intratumoural clones presenting an alternative histology to that initially diagnosed, which might become the predominant cell type and exhibit drug resistance. Blue font: lncRNA-mediated molecular events that promote lineage plasticity

Fig. 2

Mechanisms of lncRNA-mediated lineage transition. Transcription factors (such as SOX family), histone-modifying enzymes (such as enhancer of zeste homologue 2 (EZH2) and RE1-slienicng transcription factor (REST)) regulate the reprogramming tumor cells into slow-cycling, drug-tolerant states. LncRNAs such as lincRNA-p21, TUG1, linc-PINT, HOXA11-AS, SOX2-OT, FBXL19-AS1, LINC00514, FENDRR are implicated in the reprogramming process. Alterations in several key signaling pathways such as WNT-β-catenin pathway, IL-6/STAT3 pathway, NF-κB pathway and YAP pathway promote phenotypic switching upon TKI treatment. lncRNAs such as MALAT1, GHET1, SNHG1, NEAT1, H19 TNK2-AS1 are involved in these key signaling pathways. Crosstalk with the tumor microenvironment, through secretion of various cytokines from cancer-associated fibroblasts such as hepatocyte growth factor(HGF), growth arrest-specific protein 6 (GAS6), CXC-chemokine ligand 12 (CXCL12), interleukin-6 (IL-6) and transforming growth factorβ (TGFβ); cytokines from endothelial cells such as epidermal growth factor (EGF), transforming growth factor-α (TGFα), vascular endothelial growth factor (VEGF) and heparin-binding EGF-like growth factor (HB-EGF); Interluekin-6 (IL-6), VEGF from tumor-associated macrophage (TAM) controls tumor plasticity. The enhanced cell–cell adhesion via increased expression of integrin β1 and N-cadherin in tumor cells and increased extracellular matrix (ECM) stiffness via Serpin B2 can also promote tyrosine kinase inhibitors (TKI) resistance. LncRNAs involved in the M2 polarization of macrophage such as XIST and GNAS-AS1 played a part in TKI resistance. Lastly, low level of oxygen can active hypoxia-inducible factor 1α (HIF1α) in tumor cells, causing autocrine signaling by secretion of TGFα, VEGF and insulin-like growth factor (IGF-1), which promotes resistance to TKI therapy. TFs transcription factors, CAF cancer-associated fibroblasts

Fig. 3

Principal strategies to target lineage plasticity in NSCLC. Three general approaches that target lineage plasticity are listed here: preventing lineage plasticity, targeting the emerging new cell identity and reversing the lineage plasticity. a Preventing lineage plasticity may prolong the clinical response to TKI treatment. Crucial signals and molecules that regulate the survival of slow-cycling cell, for instance, chromatin landscape remodeling modulators and cell cycle-related lncRNAs can be targeted to block tumor cellular plasticity. b The emerging drug-tolerant cell identity such as SCLC and epithelial–mesenchymal transition (EMT) feature can be eliminated through targeting neuroendocrine-related lncRNAs, AXL, TGFβ and E-cadherin. c Lineage plasticity can be reverted to resensitize NSCLC to TKI. Epigenetic regulators, such as enhancer of zeste homologue 2 (EZH2) and RE1-silencing transcription factors (REST), can be targeted for reversing lineage plasticity. NSCLC non-small-cell lung cancer, SCLC small-cell lung cancer, TKI tyrosine kinase inhibitor, KDM histone demethylase, HDAC histone deacetylase, TGFβ transforming growth factor-β