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

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

  • J Med Chem. 2025 Oct 17. doi: 10.1021/acs.jmedchem.5c01495.
Bin Yang 1,  Yuna Shao 2,  Ziyun Zhou 1,  Shuo Wang 1,  Zeyi Liu 2,  Guang Hu 1 3 4 5
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Key Laboratory of Pathogen Bioscience and Anti-infective Medicine, Department of Bioinformatics and Computational Biology, School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, China.
  • 2 Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
  • 3 Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, Suzhou 215123, China.
  • 4 Key Laboratory of Alkene-carbon Fibers-Based Technology & Application for Detection of Major Infectious Diseases, Soochow University, Suzhou 215123, China.
  • 5 Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, China.
PMID: 41105954 DOI: 10.1021/acs.jmedchem.5c01495
Abstract

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.

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