肺腺癌是肺癌最常见的形式，耐药性对其治疗造成了重大障碍。本研究旨在探讨长非编码 RNA (lncRNA) 的过度表达作为一种从治疗开始就促进肿瘤细胞内在耐药性的机制。耐药持续细胞（DTP）是癌细胞的一个子集，在接触治疗药物后能够存活并增殖，使其成为癌症治疗的重要研究对象。 DTP 细胞存活的分子机制尚不完全清楚；然而，长非编码 RNA (lncRNA) 已被认为发挥着至关重要的作用。来自肺腺癌细胞系的 DTP 细胞是在单次暴露于酪氨酸激酶抑制剂（TKI；厄洛替尼或奥西替尼）后获得的。建立DTP细胞后，进行RNA测序以研究lncRNA的差异表达。一些 lncRNA 和一种 mRNA 在 DTP 细胞中过表达。在癌症基因组图谱 (TCGA) 的肺腺癌患者队列中评估了 lncRNA 的临床相关性。 RT-qPCR 验证了残留 DTP 细胞和 LUAD 活检中 lncRNA 和 mRNA 的过度表达。这些 lncRNA 的敲低增加了 DTP 细胞对治疗药物的敏感性。这项研究提供了一个机会来研究 lncRNA 在内在耐药性背后的遗传和表观遗传机制中的参与情况。已鉴定的lncRNA和CD74 mRNA可作为潜在的预后标志物或治疗靶点，以改善肺癌患者的总生存期（OS）。

Lung adenocarcinoma is the most prevalent form of lung cancer, and drug resistance poses a significant obstacle in its treatment. This study aimed to investigate the overexpression of long non-coding RNAs (lncRNAs) as a mechanism that promotes intrinsic resistance in tumor cells from the onset of treatment. Drug-tolerant persister (DTP) cells are a subset of cancer cells that survive and proliferate after exposure to therapeutic drugs, making them an essential object of study in cancer treatment. The molecular mechanisms underlying DTP cell survival are not fully understood; however, long non-coding RNAs (lncRNAs) have been proposed to play a crucial role. DTP cells from lung adenocarcinoma cell lines were obtained after single exposure to tyrosine kinase inhibitors (TKIs; erlotinib or osimertinib). After establishing DTP cells, RNA sequencing was performed to investigate the differential expression of the lncRNAs. Some lncRNAs and one mRNA were overexpressed in DTP cells. The clinical relevance of lncRNAs was evaluated in a cohort of patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA). RT-qPCR validated the overexpression of lncRNAs and mRNA in the residual DTP cells and LUAD biopsies. Knockdown of these lncRNAs increases the sensitivity of DTP cells to therapeutic drugs. This study provides an opportunity to investigate the involvement of lncRNAs in the genetic and epigenetic mechanisms that underlie intrinsic resistance. The identified lncRNAs and CD74 mRNA may serve as potential prognostic markers or therapeutic targets to improve the overall survival (OS) of patients with lung cancer.