DMEA

DMEA performs mechanism-level enrichment analysis to prioritize therapeutic candidates for drug repurposing by aggregating drugs with shared mechanisms of action (MOAs).

Key Features:

• GSEA-based enrichment: Adapts Gene Set Enrichment Analysis (GSEA) to evaluate enrichment of drug MOAs rather than individual genes.
• MOA grouping: Groups drugs by shared mechanisms of action to amplify on-target signals and reduce off-target effects.
• Input compatibility: Operates on rank-ordered drug lists including perturbagen signatures from gene expression data, drug sensitivity scores from high-throughput cancer cell line screenings, and molecular classification scores related to intrinsic and acquired drug resistance.
• Simulated-data validation: Demonstrated sensitivity and robustness on simulated datasets for detecting enriched drug MOAs.
• Experimental confirmation: Predicted senolytic MOAs were experimentally validated, including detection of senolytic effects of EGFR inhibitors in primary human mammary epithelial cells.

Scientific Applications:

• Drug repurposing prioritization: Prioritizes therapeutic candidates by identifying enriched MOAs across drug sets.
• Perturbagen signature analysis: Detects enriched MOAs from perturbagen signatures derived from gene expression data.
• Drug sensitivity analysis: Identifies MOAs associated with drug sensitivity scores from high-throughput cancer cell line screenings.
• Resistance mechanism analysis: Recovers MOAs linked to molecular classification scores of intrinsic and acquired drug resistance.
• Senescence and senolytic discovery: Identifies candidate senescence-inducing and senolytic MOAs, with validation examples such as EGFR inhibitors in primary human mammary epithelial cells.

Methodology:

Adapts Gene Set Enrichment Analysis (GSEA) to group drugs by shared MOAs, tests enrichment on simulated data, and applies the approach to three types of rank-ordered drug lists: perturbagen gene expression signatures, drug sensitivity scores from high-throughput cancer cell line screens, and molecular classification scores for drug resistance.