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.

靶向治疗在非小细胞肺癌（NSCLC）中的疗效已受到多种耐药机制的阻碍。除了靶向癌基因的突变外，可逆谱系可塑性最近还被认为在NSCLC中酪氨酸激酶抑制剂（TKI）耐药性的发展中起着作用。谱系可塑性使细胞能够从一种确定的发育途径转移到另一种途径，并且已经触发了肿瘤适应不利的微环境条件的触发，包括暴露于各种疗法。更重要的是，除了体细胞突变，谱系可塑性也被认为是肿瘤内异质性的另一个来源。谱系可塑性可以驱动NSCLC细胞达到新的细胞身份，而不再依赖于药物靶向途径。组织学转化和上皮-间质转化是NSCLC中谱系可塑性介导的TKI抗性的两个著名途径。在过去的十年中，随着疾病复发的重新活检实践的增加，已经增加了对NSCLC中谱系可塑性诱导的耐药性的认识，并增进了我们对基础生物学的理解。长的非编码RNA（lncRNA）是基因组的暗物质，能够调节NSCLC的各种恶性过程，如看不见的手。最近的证据表明，lncRNA与NSCLC的TKI耐药性有关，特别是与谱系可塑性介导的耐药性有关。在这篇综述中，我们总结了lncRNAs在NSCLC中调节谱系可塑性和TKI抗性的机制。我们还将讨论对这些主题的理解如何改变治疗策略，