A New Computational Approach to Evaluating Systemic Gene–Gene Interactions in a Pathway Affected by Drug LY294002

Abstract

In this study, we investigate how drugs systemically affect genes via pathways by integrating information from interactions between chemical compounds and molecular expression datasets, and from pathway information such as gene sets using mathematical models. First, we adopt drug-induced gene expression datasets; then, employ gene set enrichment analysis tools for selecting candidate enrichment pathways; and lastly, implement the inverse algorithm package for identifying gene–gene regulatory networks in a pathway. We tested LY294002-induced datasets of the MCF7 breast cancer cell lines, and found a CELL CYCLE pathway with 101 genes, ERBB signaling pathway consisting of 82 genes, and MTOR pathway consisting of 45 genes. We consider two interactions: quantity strength depending on number of interactions, and quality strength depending on weight of interaction as positive (+) and negative (−) interactions. Our methods revealed ANAPC1-CDK6 (−0.412) and ORC2L- CHEK1(0.951) for the CELL CYCLE pathway; INS-RPS6 (−3.125) and PRKAA2-PRKAA2 (+1.319) for the MTOR pathway; and CBLB-RPS6KB1 (−0.141), RPS6KB1-CBLC (+0.238) for the ERBB signaling pathway to be top quality interactions. Top quantity interactions discovered include 12; the CDC (−,+) gene family for the CELL CYCLE pathway, 20; PIK3 (−), 23; PIK3CG (+) for the MTOR pathway, 11; PAK (−), 10; PIK3 (+) for the ERBB signaling pathway.