Feedback regulation in cell signalling: Lessons for cancer therapeutics

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Title: Feedback regulation in cell signalling: Lessons for cancer therapeutics
Authors: Nguyen, Lan K.
Kholodenko, Boris N.
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Date: Feb-2016
Online since: 2019-04-03T07:50:40Z
Abstract: The notion of feedback is fundamental for understanding signal transduction networks. Feedback loops attenuate or amplify signals, change the network dynamics and modify the input-output relationships between the signal and the target. Negative feedback provides robustness to noise and adaptation to perturbations, but as a double-edged sword can prevent effective pathway inhibition by a drug. Positive feedback brings about switch-like network responses and can convert analog input signals into digital outputs, triggering cell fate decisions and phenotypic changes. We show how a multitude of protein-protein interactions creates hidden feedback loops in signal transduction cascades. Drug treatments that interfere with feedback regulation can cause unexpected adverse effects. Combinatorial molecular interactions generated by pathway crosstalk and feedback loops often bypass the block caused by targeted therapies against oncogenic mutated kinases. We discuss mechanisms of drug resistance caused by network adaptations and suggest that development of effective drug combinations requires understanding of how feedback loops modulate drug responses.
Funding Details: European Commission - Seventh Framework Programme (FP7)
Type of material: Journal Article
Publisher: Elsevier
Journal: Seminars in Cell & Developmental Biology
Volume: 50
Start page: 85
End page: 94
Copyright (published version): 2015 Elsevier
Keywords: Drug resistanceSignal transductionNetwork dynamicsFeedback regulationMathematical modellingNetwork analysisSystems stability
DOI: 10.1016/j.semcdb.2015.09.024
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
SBI Research Collection
Medicine Research Collection

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