title: 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 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.
authors.affiliation: Laboratory of Molecular Tumour Pathology, Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Bertram
authors.initials: B
authors.lastname: Klinger
authors.forename: Anja
authors.initials: A
authors.lastname: Sieber
authors.forename: Raphaela
authors.initials: R
authors.lastname: Fritsche-Guenther
authors.forename: Franziska
authors.initials: F
authors.lastname: Witzel
authors.forename: Leanne
authors.initials: L
authors.lastname: Berry
authors.forename: Dirk
authors.initials: D
authors.lastname: Schumacher
authors.forename: Yibing
authors.initials: Y
authors.lastname: Yan
authors.forename: Pawel
authors.initials: P
authors.lastname: Durek
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schäfer
authors.forename: Christine
authors.initials: C
authors.lastname: Sers
authors.forename: Nils
authors.initials: N
authors.lastname: Blüthgen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008957:Models, Genetic; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D060066:Protein Interaction Maps / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins