Utilising multi-modal data-driven network analysis to identify monotherapy and combinational therapy targets in SOX2-dependent squamous cell lung cancer.

Drug discovery requires understanding disease mechanisms, making the integration of multi-modal data essential. These data types, including omics, disease-associated, and pathway information, must be combined to uncover therapeutic insights. We developed iPANDDA, a computational pipeline that integrates these data through a network-based approach to predict candidate drug targets for specific diseases. We applied iPANDDA to lung squamous cell carcinoma (LUSC), a subtype of non-small cell lung cancer representing ~25% of global cases. Despite advances in cancer therapeutics, targeted treatments for LUSC remain limited, partly due to a lack of robust models to study carcinogenesis and therapeutic response. The SOX2 gene, amplified in ~50% of patients, plays a critical role in sustaining the cancer phenotype. Using iPANDDA, we identified and validated SOX2-dependent therapeutic targets. In vitro inhibition studies confirmed AKT and mTOR complexes as key monotherapy and combination therapy targets and revealed pathways for SOX2-targeted combination therapies.