DepLink

DepLink integrates heterogeneous datasets to systematically link genetic and pharmacologic dependencies in cancer research.

Key Features:

• Integrated datasets: Combines genome-wide CRISPR loss-of-function screens, high-throughput pharmacologic screens, and gene expression signatures resulting from perturbations.
• Module 1: Searches for potential inhibitors targeting a specific gene to identify drugs that phenocopy gene perturbation effects.
• Module 2: Identifies inhibitors for multiple genes to support analysis of polygenic dependencies and combination targets.
• Module 3: Explores mechanisms of action of known drugs by linking pharmacologic responses to molecular signatures.
• Module 4: Finds drugs with similar biochemical features to investigational compounds to aid analog discovery and candidate prioritization.
• Validation analysis: Links drug treatment effects to knockouts of annotated target genes, exemplified by queries using CDK6 that recovered known inhibitors and novel synergistic gene–drug partners.

Scientific Applications:

• Target identification: Prioritizes candidate drug targets by matching drug sensitivity profiles to genetic dependency data.
• Polygenic target discovery: Supports identification of combination or multi-gene therapeutic strategies by querying multiple-gene dependencies.
• Mechanism-of-action elucidation: Infers drug mechanisms by comparing pharmacologic signatures with perturbation-derived gene expression changes.
• Drug repurposing and analog discovery: Identifies compounds with similar biochemical or phenotypic profiles to investigational drugs for repurposing or lead expansion.
• Discovery of synergistic gene–drug pairs: Reveals potential synergistic interactions between gene perturbations and pharmacologic agents.

Methodology:

Integrates genome-wide CRISPR loss-of-function screens, high-throughput pharmacologic screens, and perturbation-derived gene expression signatures through four complementary query modules; validation compares drug treatment effects to annotated gene knockout phenotypes.