Analysis of Modular Hub Genes and Therapeutic Targets across Stages of Non-Small Cell Lung Cancer Transcriptome

Abstract

Non-small cell lung cancer (NSCLC), representing 85% of lung cancer cases, is characterized by its heterogeneity and progression through distinct stages. This study applied Weighted Gene Co-expression Network Analysis (WGCNA) to explore the molecular mechanisms of NSCLC and identify potential therapeutic targets. Gene expression data from the GEO database were analyzed across four NSCLC stages (NSCLC1, NSCLC2, NSCLC3, and NSCLC4), with the NSCLC2 dataset selected as the reference for module preservation analysis. WGCNA identified eight highly preserved modules-Cyan, Yellow, Red, Dark Turquoise, Turquoise, White, Purple, and Royal Blue-across datasets, which were enriched in key pathways such as Cell cycle" and "Pathways in cancer"involving processes like cell division and inflammatory responses. Hub genes CDK1 and EGFR emerged as critical regulators of tumor proliferation and immune responses. Estrogen receptor ESR1 was also highlighted correlating with improved survival outcomes suggesting its potential as a prognostic marker. Signature-based drug repurposing analysis identified promising therapeutic candidates including GW-5074 which inhibits RAF and disrupts the EGFR-RAS-RAF-MEK-ERK signaling cascade and olomoucine a CDK1 inhibitor. Additional candidates like pinocembrin which reduces NSCLC cell invasion by modulating epithelial-mesenchymal transition and citalopram an SSRI with anti-carcinogenic properties were also identified. These findings provide valuable insights into the molecular underpinnings of NSCLC and suggest new directions for therapeutic strategies through drug repurposing."