Novel molecular subtype-based precision therapy improves prognosis for lung adenocarcinoma patients

Abstract

Abstract Background Lung adenocarcinoma (LUAD) is a malignancy with a high global incidence and cancer-related mortality rate. Although various clinical trials have improved the prognosis of LUAD patients, the 5-year survival rate is still low. This study aimed to improve the prognosis of LUAD patients through molecular subtype-based precision therapy. Methods LUAD RNA sequencing (RNA-seq) data obtained from online database was used to screen for differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) combined with univariate and multifactorial COX analysis was used to identify hub prognostic genes. Based on these genes, pam clustering classified LUAD into two subtypes. The ESTIMATE, Immunophenoscore (IPS), and Microenvironment Cell Populations-counter (MCP-counter) algorithm were applied to determine the microenvironmental purity and immune response of the two subtypes. Genomic enrichment analysis (GSEA) was performed to analyze the function. Mutational difference was also explored. The effects of cisplatin and FASNi on gene expression were examined by RT-PCR. Results The results showed that LUAD patients could be divided into two subtypes. The survival rate of patients in cluster 2 was signifcantly higher than that in cluster 1 (P = 7.9e-3). Patients in cluster 2 had more immune cell infiltration, higher microenvironmental component, and higher rate of EGFR mutations (P < 0.05). In contrast, patients in cluster 1 had more fibroblast infiltration and high rate of NTRK3 mutations (P < 0.05). In addition, functional analysis suggested cluster 1 was associated with Nucleotide sequence repair, while cluster 2 mainly related to lipid metabolism and angiogenic pathways (FDR < 0.25). RT-PCR indicated that cluster1-related model genes were associated with cisplatin, cluster2-related genes were associated with EGFR-targeted therapy and lipid metabolism inhibitors. Conclusions This study showed patients in cluster 1 may benefit from anti-Nucleotide repair therapies such as platinum, radiotherapy, targeting fibroblasts, and targeting NTRK3, while patients in cluster 2 benefit from immunotherapy, anti-angiogenic, targeting lipid metabolism, and targeting EGFR therapy. This study may provide new insights to improve the overall prognosis of LUAD patients through molecular subtype-based precision therapy.