Identification and experimental verification of a novel cisplatin resistance-related lncRNA signature for predicting prognosis and immune response in lung adenocarcinoma.

BACKGROUND

Cisplatin (CDDP) resistance represents an urgent clinical challenge. Identifying CDDP-resistant lung adenocarcinoma (LUAD) patients responsive to immunotherapy through novel biomarkers is critical for improving survival outcomes.

METHODS

CDDP resistance genes were identified from RNA-seq data of A549 cells in the GEO database. RNA sequencing, genetic mutations, and clinical data of LUAD patients were obtained from TCGA. Patients were split into training and validation cohorts. A prognostic model was developed using LASSO and multivariate Cox regression, with validation in both cohorts. Tumor mutation burden (TMB), immune activity, and functional enrichment analyses (GO, KEGG) were performed to explore the link between lncRNA and CDDP resistance.

RESULTS

Twenty-three CDDP resistance-associated genes were identified from GEO. Co-expression analysis revealed 507 CDDP resistance-linked lncRNAs. Cox regression analysis identified three CDDP resistance-related lncRNAs: ARAP1-AS2, LINC01843, and LINC02198. RT-PCR verified these lncRNAs and representative mRNAs (KIF21B, B3GNT3, PLXNA2). Patients stratified by median risk score showed significantly worse overall survival (OS) and higher mortality in high-risk groups. Univariate/multivariate Cox analyses confirmed the risk score as an independent prognostic factor. A nomogram predicted LUAD survival outcomes. Low-risk patients exhibited significantly lower TMB than high-risk counterparts, with low-risk/high-TMB patients showing optimal OS. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm revealed significant differences in immune dysfunction, CD8+ T cells, cancer-associated fibroblasts (CAF), and tumor-associated macrophages (TAM-M2) between risk groups.

CONCLUSION

These three CDDP resistance-associated lncRNAs including ARAP1-AS2, LINC01843, and LINC02198, serve as reliable prognostic biomarkers for LUAD. The findings provide insights for immunotherapeutic strategies and personalized treatment development.