Nguyen2016 - Feedback regulation in cell signalling: Lessons for cancer therapeutics

Feedback regulation in cell signalling:
Lessons for cancer therapeutics

This model is described in the article:

Feedback regulation in cell
signalling: Lessons for cancer therapeutics.

Nguyen LK, Kholodenko BN.
Semin. Cell Dev. Biol. 2016 Feb; 50:
85-94
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.

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