Non-monotonic dynamics and crosstalk in signaling pathways and their implications for pharmacology

van Wijk, R.; Tans, S. J.; ten Wolde, P. R.; Mashaghi, A.
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.
Year:
2015
Type of Publication:
Article
Journal:
Sci Rep
Volume:
5
Pages:
11376
Month:
June
Note:
[PubMed Central:\href{https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155565}{PMC5155565}] [DOI:\href{https://dx.doi.org/10.1038/srep11376}{10.1038/srep11376}] [PubMed:\href{https://www.ncbi.nlm.nih.gov/pubmed/26087464}{26087464}]
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