RT Journal Article
T1 Drug treatment efficiency depends on the initial state of activation in nonlinear pathways
A1 Doldan Martelli, Victoria Lucia
A1 Miguez, David G
AB An accurate prediction of the outcome of a given drug treatment requires quantitative values for all parameters and concentrations involved as well as a detailed characterization of the network of interactions where the target molecule is embedded. Here, we present a high-throughput in silico screening of all potential networks of three interacting nodes to study the effect of the initial conditions of the network in the efficiency of drug inhibition. Our study shows that most network topologies can induce multiple dose-response curves, where the treatment has an enhanced, reduced or even no effect depending on the initial conditions. The type of dual response observed depends on how the potential bistable regimes interplay with the inhibition of one of the nodes inside a nonlinear pathway architecture. We propose that this dependence of the strength of the drug on the initial state of activation of the pathway may be affecting the outcome and the reproducibility of drug studies and clinical trials.
PB Nature Research
SN 2045-2322
YR 2018
FD 2018-08-21
LK https://hdl.handle.net/10016/28583
UL https://hdl.handle.net/10016/28583
LA eng
NO This work has been supported by the Ministry of Science and Technology of Spain via a Ramón y Cajal Fellowship (Ref. RYC-2010-07450), a grant from Plan Nacional framework (Ref. BFU2011-30303 and & BFU2014-53299-P) and a FPU fellowship. We thank Raúl Guantes, Juan Díaz Colunga, Marta Ibañes, Rosa Martínez Corral, Saúl Ares and Katherine Gonzales for invaluable help and technical assistance.
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RD 1 jun. 2024