Journal Article

Multi-omics protein signaling networks identify sex-specific therapeutic candidates in lung adenocarcinoma

Chen, Chen, Padi, Megha, Fischer, Jonas, Fanfani, Viola, DeMeo, Dawn L., Saha, Enakshi, Quackenbush, John, Ben Guebila, Marouen, Shutta, Katherine H., Lopes-Ramos, Camila M., Glass, Kimberly

2025

Overview

Background Lung adenocarcinoma shows distinct differences between males and females in incidence, prognosis, and treatment response, suggesting unique molecular mechanisms that remain underexplored. This study aims to identify sex-specific molecular signatures and therapeutic targets in lung adenocarcinoma using multi-omics approaches to inform personalized treatment strategies. Methods We conducted an integrative analysis of transcriptomic and proteomic data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) datasets, comparing male and female lung adenocarcinoma profiles. Transcription factor activity was assessed using TIGER on gene expression data, while kinase activity was evaluated with PTM-SEA on proteomic data. These results were combined to build a kinase-transcription factor signaling network. Potential sex-specific drugs were identified using the PRISM drug screening database. Results The analysis revealed significant sex-based differences in transcription factor and kinase activity. Notably, NR3C1, AR, and AURKA exhibited sex-biased expression and activity. The constructed signaling network highlighted druggable pathways linked to cancer-related processes, with distinct profiles in males and females. PRISM screening identified glucocorticoid receptor agonists and aurora kinase inhibitors as promising sex-specific therapeutic candidates. Conclusions Our findings underscore the importance of considering sex differences in lung adenocarcinoma molecular profiles. The integration of transcriptomic and proteomic data reveals sex-specific pathways and potential therapies, paving the way for personalized treatment approaches tailored to male and female patients. Highlights Identified sex-specific molecular differences in lung adenocarcinoma using gene and protein data. Found women have stronger immune responses, linked to better survival outcomes. Discovered sixteen drugs with different effectiveness in men versus women, including aurora kinase inhibitors. Integrated multi-omics approach revealed new pathways for personalized, sex-specific treatments. Highlights the need to consider biological sex to improve cancer therapy outcomes. Plain English Summary Lung cancer, specifically lung adenocarcinoma, affects men and women differently in terms of how often it occurs, how it progresses, and how well treatments work. These differences likely come from a mix of genetics, hormones, and lifestyle factors, but the exact reasons are not fully understood. Our study used advanced tools to compare the molecular makeup of lung tumors in men and women, looking at both gene activity and protein function. We found important differences in how certain proteins and genes work together in men versus women, including differences that influence cancer growth and immune responses. For example, women showed stronger immune activity linked to better survival, while men and women responded differently to certain drugs. By identifying these differences, we discovered potential new treatments, such as drugs targeting specific proteins, that might work better for men or women. This research shows that considering sex differences is key to developing better, personalized treatments for lung cancer, which could improve outcomes for all patients.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adenocarcinoma / Adenocarcinoma of Lung - drug therapy / Adenocarcinoma of Lung - genetics / Adenocarcinoma of Lung - metabolism / Anopheles / Antimitotic agents / Antineoplastic agents / Aurora kinase / B cells / Biomedical and Life Sciences / Biomedicine / Cancer / Datasets / Drug development / Drug repurposing / Drug screening / Endocrinology / Female / Females / Fluoxymesterone / Gender differences / Gene expression / Genes / Genetic aspects / Genetic transcription / Genomes / Glucocorticoid receptors / Health aspects / Hormones / Human Physiology / Humans / Lung adenocarcinoma / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lungs / Male / Molecular modelling / Multi-omics / Multiomics / Post-translational modifications / Protein signaling network / Proteomics / Sex Characteristics / Sex differences / Signal Transduction / Therapeutic targets / Transcriptome / Transcriptomics