Feedback regulation in cell signalling: Lessons for cancer therapeutics

Semin Cell Dev Biol. 2016 Feb:50:85-94. doi: 10.1016/j.semcdb.2015.09.024. Epub 2015 Oct 19.

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.

Keywords: Drug resistance, Signal transduction, Network dynamics; Feedback regulation; Mathematical modelling; Network analysis; Systems stability.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Drug Resistance, Neoplasm / drug effects
  • Feedback, Physiological* / drug effects
  • Homeostasis / drug effects
  • Humans
  • Neoplasms / drug therapy*
  • Signal Transduction* / drug effects

Substances

  • Antineoplastic Agents