Personalized Network Modeling of the Pan-Cancer Patient and Cell Line Interactome

A BSTRACT Purpose Personalized network inference on diverse clinical and in vitro model systems across cancer types can be used to delineate specific regulatory mechanisms, uncover drug targets and pathways, and develop individualized predictive models in cancer. Datasets and methods We developed TransPRECISE, a multi-scale Bayesian network modeling framework, to analyze the pan-cancer patient and cell line interactome to identify differential and conserved intra-pathway activities, globally assess cell lines as representative models for patients and develop drug sensitivity prediction models. We assessed pan-cancer pathway activities for a large cohort of patient samples (>7700) from The Cancer Proteome Atlas across ≥30 tumor types and a set of 640 cancer cell lines from the M.D. Anderson Cell Lines Project spanning16 lineages, and ≥250 cell lines’ response to >400 drugs. Results TransPRECISE captured differential and conserved proteomic network topologies and pathway circuitry between multiple patient and cell line lineages: ovarian and kidney cancers shared high levels of connectivity in the hormone receptor and receptor tyrosine kinase pathways, respectively, between the two model systems. Our tumor stratification approach found distinct clinical subtypes of the patients represented by different sets of cell lines: head and neck patient tumors were classified into two different subtypes that are represented by head and neck and esophagus cell lines, and had different prognostic patterns (456 vs. 654 days of median overall survival; P=0.02). The TransPRECISE-based sample-specific pathway scores achieved high predictive accuracy for drug sensitivities in cell lines across multiple drugs (median AUC >0.8). Conclusion Our study provides a generalizable analytical framework to assess the translational potential of preclinical model systems and guide pathway-based personalized medical decision-making, integrating genomic and molecular data across model systems.