Systems Biology-Based Drug Repositioning Identifies Extracellular Matrix Module as a Therapeutic Target in Lung Squamous Cell Carcinoma

Systematic proteomic comparisons across cancer subtypes
provide
insights into tumor heterogeneity and accelerate discovery of therapeutic
targets and drug repositioning. Here, we present a novel computational
framework, signature-network-perturbation- based drug repositioning
(SnpDR), integrating proteomic and pharmacogenomic data through differential
modular analysis, drug response network construction, and multiscale
perturbation response scanning. Applying SnpDR to compare the proteomic
landscapes of lung adenocarcinoma and lung squamous cell carcinoma
(LSCC), we identified the extracellular matrix (ECM) module as a central
hub in LSCC, while LAMA1 emerged as a novel drug target. In
vitro and in vivo experiments validated
two repositioned drugs, Fingolimod and Piperlongumine, both targeting
ECM components, significantly inhibited LSCC cell growth, proliferation
and migration at concentrations below 10 μM. These results provide
compelling evidence for the power of systems biology to identify subtype-specific
therapeutic vulnerabilities. Our findings highlight a promising framework
for precision oncology and underscore the potential of ECM-targeted
interventions in LSCC.