Network quantification of EGFR signaling unveils potential for targeted combination therapy
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 combinatori...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2013-06-01
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| Series: | Molecular Systems Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/msb.2013.29 |
| _version_ | 1826990456696733696 |
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| author | Bertram Klinger Anja Sieber Raphaela Fritsche‐Guenther Franziska Witzel Leanne Berry Dirk Schumacher Yibing Yan Pawel Durek Mark Merchant Reinhold Schäfer Christine Sers Nils Blüthgen |
| author_facet | Bertram Klinger Anja Sieber Raphaela Fritsche‐Guenther Franziska Witzel Leanne Berry Dirk Schumacher Yibing Yan Pawel Durek Mark Merchant Reinhold Schäfer Christine Sers Nils Blüthgen |
| author_sort | Bertram Klinger |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T21:49:47Z |
| format | Article |
| id | doaj.art-a4ed5dbe243d4ea28f53fa9649700665 |
| institution | Directory Open Access Journal |
| issn | 1744-4292 |
| language | English |
| last_indexed | 2025-02-18T08:20:51Z |
| publishDate | 2013-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj.art-a4ed5dbe243d4ea28f53fa96497006652024-11-03T12:55:57ZengSpringer NatureMolecular Systems Biology1744-42922013-06-019111410.1038/msb.2013.29Network quantification of EGFR signaling unveils potential for targeted combination therapyBertram Klinger0Anja Sieber1Raphaela Fritsche‐Guenther2Franziska Witzel3Leanne Berry4Dirk Schumacher5Yibing Yan6Pawel Durek7Mark Merchant8Reinhold Schäfer9Christine Sers10Nils Blüthgen11Laboratory of Molecular Tumour Pathology, Institute of Pathology, Charité ‐ Universitätsmedizin BerlinLaboratory of Molecular Tumour Pathology, Institute of Pathology, Charité ‐ Universitätsmedizin BerlinLaboratory of Molecular Tumour Pathology, Institute of Pathology, Charité ‐ Universitätsmedizin BerlinLaboratory of Molecular Tumour Pathology, Institute of Pathology, Charité ‐ Universitätsmedizin BerlinDepartment of Translation Oncology, Genentech, Inc.Laboratory of Molecular Tumour Pathology, Institute of Pathology, Charité ‐ Universitätsmedizin BerlinOncology Biomarker Development, Genentech, Inc.Laboratory of Molecular Tumour Pathology, Institute of Pathology, Charité ‐ Universitätsmedizin BerlinDepartment of Translation Oncology, Genentech, Inc.Laboratory of Molecular Tumour Pathology, Institute of Pathology, Charité ‐ Universitätsmedizin BerlinLaboratory of Molecular Tumour Pathology, Institute of Pathology, Charité ‐ Universitätsmedizin BerlinLaboratory of Molecular Tumour Pathology, Institute of Pathology, Charité ‐ Universitätsmedizin BerlinAbstract 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.https://doi.org/10.1038/msb.2013.29cancerEGFR signalingmathematical modelingmodular response analysissignal transduction |
| spellingShingle | Bertram Klinger Anja Sieber Raphaela Fritsche‐Guenther Franziska Witzel Leanne Berry Dirk Schumacher Yibing Yan Pawel Durek Mark Merchant Reinhold Schäfer Christine Sers Nils Blüthgen Network quantification of EGFR signaling unveils potential for targeted combination therapy Molecular Systems Biology cancer EGFR signaling mathematical modeling modular response analysis signal transduction |
| title | Network quantification of EGFR signaling unveils potential for targeted combination therapy |
| title_full | Network quantification of EGFR signaling unveils potential for targeted combination therapy |
| title_fullStr | Network quantification of EGFR signaling unveils potential for targeted combination therapy |
| title_full_unstemmed | Network quantification of EGFR signaling unveils potential for targeted combination therapy |
| title_short | Network quantification of EGFR signaling unveils potential for targeted combination therapy |
| title_sort | network quantification of egfr signaling unveils potential for targeted combination therapy |
| topic | cancer EGFR signaling mathematical modeling modular response analysis signal transduction |
| url | https://doi.org/10.1038/msb.2013.29 |
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