Open AccessNetwork quantification of EGFR signaling unveils potential for targeted combination therapy
Author(s) -
Klinger Bertram,
Sieber Anja,
FritscheGuenther Raphaela,
Witzel Franziska,
Berry Leanne,
Schumacher Dirk,
Yan Yibing,
Durek Pawel,
Merchant Mark,
Schäfer Reinhold,
Sers Christine,
Blüthgen Nils
Publication year - 2013
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.1038/msb.2013.29
Subject(s) - kras , mapk/erk pathway , protein kinase b , epidermal growth factor receptor , pi3k/akt/mtor pathway , biology , cancer research , egfr inhibitors , targeted therapy , signal transduction , cancer , computational biology , colorectal cancer , microbiology and biotechnology , genetics
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.