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Abstract:

Background: It has been shown in experimental and theoretical work that covalently modified signaling cascades naturally exhibit bidirectional signal propagation via a phenomenon known as retroactivity. An important consequence of retroactivity, which arises due to enzyme sequestration in covalently modified signaling cascades, is that a downstream perturbation can produce a response in a component upstream of the perturbation without the need for explicit feedback connections. Retroactivity may, therefore, play an important role in the cellular response to a targeted therapy. Kinase inhibitors are a class of targeted therapies designed to interfere with a specific kinase molecule in a dysregulated signaling pathway. While extremely promising as anti-cancer agents, kinase inhibitors may produce undesirable off-target effects by non-specific interactions or pathway cross-talk. We hypothesize that targeted therapies such as kinase inhibitors can produce off-target effects as a consequence of retroactivity alone.Results: We used a computational model and a series of simple signaling motifs to test the hypothesis. Our results indicate that within physiologically and therapeutically relevant ranges for all parameters, a targeted inhibitor can naturally induce an off-target effect via retroactivity. The kinetics governing covalent modification cycles in a signaling network were more important for propagating an upstream off-target effect in our models than the kinetics governing the targeted therapy itself. Our results also reveal the surprising and crucial result that kinase inhibitors have the capacity to turn "on" an otherwise "off" parallel cascade when two cascades share an upstream activator.Conclusions: A proper and detailed characterization of a pathway's structure is important for identifying the optimal protein to target as well as what concentration of the targeted therapy is required to modulate the pathway in a safe and effective manner. We believe our results support the position that such characterizations should consider retroactivity as a robust potential source of off-target effects induced by kinase inhibitors and other targeted therapies. © 2011 Wynn et al; licensee BioMed Central Ltd.

Registro:

Documento: Artículo
Título:Kinase inhibitors can produce off-target effects and activate linked pathways by retroactivity
Autor:Wynn, M.L.; Ventura, A.C.; Sepulchre, J.A.; García, H.J.; Merajver, S.D.
Filiación:Center for Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, United States
Laboratorio de Fisiología y Biología Molecular, Departamento de Fisiología, Biología Molecular y Celular,r IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturale, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, Buenos Aires, Argentina
Institut Non Linéaire de Nice, Université de Nice Sophia-Antipolis, UMR CNRS 6618, Valbonne, France
Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI, United States
Department of Internal Medicine, Division of Hematology and Oncology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
Palabras clave:protein kinase inhibitor; article; biological model; computer simulation; metabolism; signal transduction; systems biology; Computer Simulation; Metabolic Networks and Pathways; Models, Biological; Protein Kinase Inhibitors; Signal Transduction; Systems Biology
Año:2011
Volumen:5
DOI: http://dx.doi.org/10.1186/1752-0509-5-156
Título revista:BMC Systems Biology
Título revista abreviado:BMC Syst. Biol.
ISSN:17520509
CAS:Protein Kinase Inhibitors
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_17520509_v5_n_p_Wynn

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Citas:

---------- APA ----------
Wynn, M.L., Ventura, A.C., Sepulchre, J.A., García, H.J. & Merajver, S.D. (2011) . Kinase inhibitors can produce off-target effects and activate linked pathways by retroactivity. BMC Systems Biology, 5.
http://dx.doi.org/10.1186/1752-0509-5-156
---------- CHICAGO ----------
Wynn, M.L., Ventura, A.C., Sepulchre, J.A., García, H.J., Merajver, S.D. "Kinase inhibitors can produce off-target effects and activate linked pathways by retroactivity" . BMC Systems Biology 5 (2011).
http://dx.doi.org/10.1186/1752-0509-5-156
---------- MLA ----------
Wynn, M.L., Ventura, A.C., Sepulchre, J.A., García, H.J., Merajver, S.D. "Kinase inhibitors can produce off-target effects and activate linked pathways by retroactivity" . BMC Systems Biology, vol. 5, 2011.
http://dx.doi.org/10.1186/1752-0509-5-156
---------- VANCOUVER ----------
Wynn, M.L., Ventura, A.C., Sepulchre, J.A., García, H.J., Merajver, S.D. Kinase inhibitors can produce off-target effects and activate linked pathways by retroactivity. BMC Syst. Biol. 2011;5.
http://dx.doi.org/10.1186/1752-0509-5-156