title: Non-monotonic dynamics and crosstalk in signaling pathways and their implications for pharmacology.
abstract: Currently, drug discovery approaches commonly assume a monotonic dose-response relationship. However, the assumption of monotonicity is increasingly being challenged. Here we show that for two simple interacting linear signaling pathways that carry two different signals with different physiological responses, a non-monotonic input-output relation can arise with simple network topologies including coherent and incoherent feed-forward loops. We show that non-monotonicity of the response functions has severe implications for pharmacological treatment. Fundamental constraints are imposed on the effectiveness and toxicity of any drug independent of its chemical nature and selectivity due to the specific network structure.
authors.affiliation: 1] FOM Institute AMOLF, Science Park 104, 1098 XG Amsterdam, The Netherlands [2] Department of Bionanoscience, Kavli Institute of Nanoscience, Delft University of Technology, Lorentzweg 1, 2628 CJ Delft, the Netherlands.
authors.forename: Roeland
authors.initials: R
authors.lastname: van Wijk
authors.affiliation: FOM Institute AMOLF, Science Park 104, 1098 XG Amsterdam, The Netherlands.
authors.forename: Sander J
authors.initials: SJ
authors.lastname: Tans
authors.affiliation: FOM Institute AMOLF, Science Park 104, 1098 XG Amsterdam, The Netherlands.
authors.forename: Pieter Rein
authors.initials: PR
authors.lastname: ten Wolde
authors.affiliation: Harvard Medical School, 25 Shattuck St, Boston, MA 02115, USA.
authors.forename: Alireza
authors.initials: A
authors.lastname: Mashaghi
mesh_terms: D000465:Algorithms; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D008954:Models, Biological; D010600:Pharmacology / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects*