Lnc-TMEM132D-AS1 Confers Acquired Resistance to Osimertinib in Non-Small-Cell Lung Cancer

Abstract Objective: Acquired resistance is a major obstacle to the therapeutic efficacy of osimertinib in non-small-cell lung cancer (NSCLC). Current knowledge about the role of long non-coding RNAs (lncRNAs) in this phenomenon is insufficient. Here, we aim to identify candidate lncRNAs associated with acqured resistance to osimertinib in NSCLC, and explore the role and underlying mechanism of one of these lncRNAs, lnc-TMEM132D-AS1. Methods and Results: RNA Sequencing (RNA-Seq) and quantitative real-time PCR (qPCR) were used to screen and validate the differentially expressed lncRNAs between osimertinib-sensitive and -resistant NSCLC cell lines. Lnc-TMEM132D-AS1 was screened out, and was found to be upregulated in the osimertinib-resistant NSCLC cell lines as well as the plasma of NSCLC patients. Results from CCK-8, colony formation, flow cytometry assays showed that lnc-TMEM132D-AS1 knockdown significantly increased the sensitivity of osimertinib-resistant NSCLC cells to osimertinib. After identifying the cytoplasmic localization of lnc-TMEM132D-AS1, a functional lnc-TMEM132D-AS1-miRNA-mRNA interaction network and protein-protein interaction (PPI) network were constructed to analyze its putative target genes and biological functions. Using qPCR and TISIDB database analysis, ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1) was confirmed to be a target mRNA of lnc-TMEM132D-AS1, and was associated with tumor infiltration of immunosuppressive cells and poor prognosis in patients with NSCLC. Conclusion: In summary, lnc-TMEM132D-AS1 plays a crucial role in osimertinib resistance. It may serve as a prognostic biomarker and a potential therapeutic target for acquired resistance to osimertinib in NSCLC.