Network quantification of EGFR signaling unveils potential for targeted combination therapy
Open Access
- 1 January 2013
- journal article
- Published by Springer Science and Business Media LLC in Molecular Systems Biology
- Vol. 9 (1), 673
- https://doi.org/10.1038/msb.2013.29
Abstract
The epidermal growth factor receptor (EGFR) signaling network is activated in most solid tumors, and small‐molecule drugs targeting this network are increasingly available. However, often only specific combinations of inhibitors are effective. Therefore, the prediction of potent combinatorial treatments is a major challenge in targeted cancer therapy. In this study, we demonstrate how a model‐based evaluation of signaling data can assist in finding the most suitable treatment combination. We generated a perturbation data set by monitoring the response of RAS/PI3K signaling to combined stimulations and inhibitions in a panel of colorectal cancer cell lines, which we analyzed using mathematical models. We detected that a negative feedback involving EGFR mediates strong cross talk from ERK to AKT. Consequently, when inhibiting MAPK, AKT activity is increased in an EGFR‐dependent manner. Using the model, we predict that in contrast to single inhibition, combined inactivation of MEK and EGFR could inactivate both endpoints of RAS, ERK and AKT. We further could demonstrate that this combination blocked cell growth in BRAF‐ as well as KRAS‐mutated tumor cells, which we confirmed using a xenograft model.Keywords
This publication has 68 references indexed in Scilit:
- Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling NetworksCell, 2012
- Combined experimental and computational analysis of DNA damage signaling reveals context‐dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stressMolecular Systems Biology, 2012
- Reverse engineering a hierarchical regulatory network downstream of oncogenic KRASMolecular Systems Biology, 2012
- Hallmarks of Cancer: The Next GenerationCell, 2011
- Strong negative feedback from Erk to Raf confers robustness to MAPK signallingMolecular Systems Biology, 2011
- PI3K/Akt-sensitive MEK-independent compensatory circuit of ERK activation in ER-positive PI3K-mutant T47D breast cancer cellsCellular Signalling, 2010
- Discrete logic modelling as a means to link protein signalling networks with functional analysis of mammalian signal transductionMolecular Systems Biology, 2009
- Recurrent design patterns in the feedback regulation of the mammalian signalling networkMolecular Systems Biology, 2008
- Models from experiments: combinatorial drug perturbations of cancer cellsMolecular Systems Biology, 2008
- A comprehensive pathway map of epidermal growth factor receptor signalingMolecular Systems Biology, 2005