Another HER-family signaling model


There has been a great deal of interest in the signaling of the HER family of receptors as a result of the central role that they appear to take in the proliferation of certain epithelial cancers. Some biotechnology companies have even built innovative portfolios of biotherapeutics around some of the q quantitative ideas that have been derived from such models.

Now a new study published in the August 2013 issue of PLOS Computational Biology, takes the modeling of the complex HER family signaling pathways, a step further. with a model based upon a comprehensive data set comprising the relative abundance and phosphorylation levels from a panel of human, mammary epithelial cells. Here is an excerpt from author's own summary of the article.

"We constructed an integrated mathematical model of HER activation, and trafficking to quantitatively link receptor expression levels to dimerization and activation. We parameterized the model with a comprehensive set of HER phosphorylation and abundance data collected in a panel of human mammary epithelial cells expressing varying levels of EGFR/HER1, HER2 and HER3. Although parameter estimation yielded multiple solutions, predictions for dimer phosphorylation were in agreement with each other. We validated the model using experiments where pertuzumab was used to block HER2 dimerization. We used the model to predict HER dimerization and activation patterns in a panel of human mammary epithelial cells lines with known HER expression levels in response to stimulations with ligands EGF and HRG. Simulations over the range of expression levels seen in various cell lines indicate that: i) EGFR phosphorylation is driven by HER1-HER1 and HER1-HER2 dimers, and not HER1-HER3 dimers, ii) HER1-HER2 and HER2-HER3 dimers both contribute significantly to HER2 activation with the EGFR expression level determining the relative importance of these species, and iii) the HER2-HER3 dimer is largely responsible for HER3 activation. The model can be used to predict phosphorylated dimer levels for any given HER expression profile. This information in turn can be used to quantify the potencies of the various HER dimers, and can potentially inform personalized therapeutic approaches."

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