Skip to main content

Advertisement

Applications of sensitivity analysis for drug discovery and development in the ErbB receptor network

Article metrics

  • 1064 Accesses

Receptor-mediated signaling networks are very attractive targets for the development of oncology therapeutics. However, the complexity of these networks, characterized by redundancy, cross-talk, and non-linearity, hinders the generation of reliable qualitative insight into how to develop the most effective therapeutic and deliver it to the right patient.

We are using quantitative biochemical network models of receptor signaling to yield significant improvements in drug design and decision-making throughout the development of our therapeutics. As an example, we have developed a model of the ErbB receptor network that includes ErbB1-4, ligand-receptor binding of different ErbB ligands, receptor trafficking, and intracellular signal transfer leading to ERK and Akt phosphorylation. The model is first trained using quantitative experimental data and then our in silico predictions are verified by an independent set of experiments.

Using this validated biochemical network model, we present methodologies for using local and global sensitivity analyses as in silico drug discovery tools. The application of sensitivity analysis allows us to gain quantitative insights into important issues including network topology and the importance of cellular heterogeneity with respect to protein expression. We show how these insights find application in drug targeting and biomarker identification.

Author information

Correspondence to B Harms or R Paxson.

Rights and permissions

Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Keywords

  • Sensitivity Analysis
  • Drug Discovery
  • Signaling Network
  • Attractive Target
  • Signal Transfer