Perez-Medina Mario, Lopez-Gonzalez Jose S, Benito-Lopez Jesus J, Ávila-Ríos Santiago, Soto-Nava Maribel, Matias-Florentino Margarita, Méndez-Tenorio Alfonso, Galicia-Velasco Miriam, Chavez-Dominguez Rodolfo, Meza-Toledo Sergio E, Aguilar-Cazares Dolores
Laboratorio de Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Ciudad de Mexico 14080, Mexico.
Laboratorio de Quimioterapia Experimental, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Ciudad de Mexico 14080, Mexico.
Cancers (Basel). 2024 Jul 8;16(13):2490. doi: 10.3390/cancers16132490.
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.
肺腺癌是肺癌最常见的形式，耐药性是其治疗中的一个重大障碍。本研究旨在调查长链非编码RNA（lncRNA）的过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。耐药持久性（DTP）细胞是癌细胞的一个亚群，在接触治疗药物后存活并增殖，使其成为癌症治疗中一个重要的研究对象。DTP细胞存活的分子机制尚未完全了解；然而，长链非编码RNA（lncRNA）已被认为发挥关键作用。单次暴露于酪氨酸激酶抑制剂（TKIs；厄洛替尼或奥希替尼）后，从肺腺癌细胞系中获得DTP细胞。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。在来自癌症基因组图谱（TCGA）的一组肺腺癌患者中评估了lncRNA的临床相关性。RT-qPCR验证了lncRNA和mRNA在残余DTP细胞和肺腺癌活检组织中的过表达。敲低这些lncRNA可增加DTP细胞对治疗药物的敏感性。本研究为研究lncRNA参与内在耐药性的遗传和表观遗传机制提供了一个机会。鉴定出的lncRNA和CD74 mRNA可能作为潜在的预后标志物或治疗靶点，以提高肺癌患者的总生存期（OS）。
