Feedback regulation in cell signalling: Lessons for cancer therapeutics.
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.
Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, VIC 3800, Australia. Electronic address: lan.k.nguyen@monash.edu.
Lan K
LK
Nguyen
Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland; School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland. Electronic address: boris.kholodenko@ucd.ie.
Boris N
BN
Kholodenko
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D025461:Feedback, Physiological / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents
Drug resistance, Signal transduction, Network dynamics; Feedback regulation; Mathematical modelling; Network analysis; Systems stability