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Proteins, drug targets and the mechanisms they control: the simple truth about complex networks

Abstract

Realizing the promise of molecularly targeted inhibitors for cancer therapy will require a new level of knowledge about how a drug target is wired into the control circuitry of a complex cellular network. Here we review general homeostatic principles of cellular networks that enable the cell to be resilient in the face of molecular perturbations, while at the same time being sensitive to subtle input signals. Insights into such mechanisms may facilitate the development of combination therapies that take advantage of the cellular control circuitry, with the aim of achieving higher efficacy at a lower drug dosage and with a reduced probability of drug-resistance development.

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Figure 1: An example of a composite feedback control module.
Figure 2: A minimal network representation for the dual regulation of IRS1 activity by AKT.
Figure 3: A schematic depicting the four classes of targeted therapy for the composite network motif regulating insulin receptor substrate 1 (IRS1) activity.
Figure 4: A comparison of four molecularly targeted therapies for the composite insulin receptor substrate 1 (IRS1) regulatory motif as illustrated in figure 3.
Figure 5: A simple network schematic for a kinase cascade regulated by an oncoprotein on which cell viability is strictly dependent.
Figure 6: Network output corresponding to the reaction scheme and mathematical model outlined in figure 5.
Figure 7: Combination therapies and their potential to combat the problem of tumour recurrence following a successful therapy.

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Correspondence to Robyn P. Araujo.

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All the author are inventors on university-owned patent applications and may be eligible for a share of royalty payments. E.F.P. and L.A.L. are shareholders in Theranostics Health LLC.

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DATABASES

OMIM

Chronic myelogenous leukaemia

non-small-cell lung cancer

FURTHER INFORMATION

The center for Applied Proteomics and Molecular Medicine

Glossary

Cellular mechanism

A control mechanism such as a negative- or positive-feedback loop, or a negative- or positive-feedforward loop, which overarches a potentially large number of protein–protein interactions comprising a pathway, so as to elicit a specific behaviour (for example, adaptation, oscillations or bistable switching) from that pathway.

Control system

A cellular control system is a group of proteins and/or other cellular molecules that interact to regulate their own activity, or that of another cellular system.

Nodes

A subset of proteins selected from a potentially vast network of protein–protein interactions to represent a model of the signalling network.

Protein interactome

The full set of possible protein–protein interactions in a cell.

System

A cellular system is a collection of cellular molecules, for example, proteins, that are related in such a manner as to form a whole or a unit.

Ultrasensitivity

An output response that is more sensitive to change in stimulus than the Michaelis–Menten response. An ultrasensitive response is therefore sigmoidal rather than hyperbolic.

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Araujo, R., Liotta, L. & Petricoin, E. Proteins, drug targets and the mechanisms they control: the simple truth about complex networks. Nat Rev Drug Discov 6, 871–880 (2007). https://doi.org/10.1038/nrd2381

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