NEM-Tar: A Probabilistic Graphical Model for Cancer Regulatory Network Inference and Prioritization of Potential...

Targeted therapy has been widely adopted as an effective treatment strategy to battle against cancer. However, cancers are not single disease entities, but comprising multiple molecularly distinct subtypes, and the heterogeneity nature prevents precise selection of patients for optimized therapy. Dissecting cancer subtype-specific signaling pathways is crucial to pinpointing dysregulated genes for the prioritization of novel therapeutic targets. Nested effects models (NEMs) are a group of graphical models that encode subset relations between observed downstream effects under perturbations to upstream signaling genes, providing a prototype for mapping the inner workings of the cell. In this study, we developed NEM-Tar, which extends the original NEMs to predict drug targets by incorporating causal information of (epi)genetic aberrations for signaling pathway inference. An information theory-based score, weighted information gain (WIG), was proposed to assess the impact of signaling genes on a specific downstream biological process of interest. Subsequently, we conducted simulation studies to compare three inference methods and found that the greedy hill-climbing algorithm demonstrated the highest accuracy and robustness to noise. Furthermore, two case studies were conducted using multi-omics data for colorectal cancer (CRC) and gastric cancer (GC) in the TCGA database. Using NEM-Tar, we inferred signaling networks driving the poor-prognosis subtypes of CRC and GC, respectively. Our model prioritized not only potential individual drug targets such as HER2, for which FDA-approved inhibitors are available but also the combinations of multiple targets potentially useful for the design of combination therapies.