Systems models of biological networks show promise for informing drug target selection/qualification, identifying lead compounds and factors regulating disease progression, rationalizing combinatorial regimens, and explaining sources of inter-subject variability and adverse drug reactions. In this study, logic-based modeling of signal transduction pathways in U266 multiple myeloma (MM) cells was used to guide the development of a simple dynamical model linking bortezomib exposure to cellular outcomes. Bortezomib is a commonly used first-line agent in MM treatment; however, knowledge of the signal transduction pathways regulating bortezomib-mediated cell cytotoxicity is incomplete. A Boolean network model of 66 nodes was constructed that includes major survival and apoptotic pathways and was updated using responses to several chemical probes. Simulated responses to bortezomib were in good agreement with experimental data, and a reduction algorithm was used to identify key signaling proteins.
See article at J Pharmacol Exp Ther 2015, 354:448–458.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics