Models from experiments: Combinatorial drug perturbations of cancer cells Journal Article
| Authors: | Nelander, S.; Wang, W.; Nilsson, B.; She, Q. B.; Pratilas, C.; Rosen, N.; Gennemark, P.; Sander, C. |
| Article Title: | Models from experiments: Combinatorial drug perturbations of cancer cells |
| Abstract: | We present a novel method for deriving network models from molecular profiles of perturbed cellular systems. The network models aim to predict quantitative outcomes of combinatorial perturbations, such as drug pair treatments or multiple genetic alterations. Mathematically, we represent the system by a set of nodes, representing molecular concentrations or cellular processes, a perturbation vector and an interaction matrix. After perturbation, the system evolves in time according to differential equations with built-in nonlinearity, similar to Hopfield networks, capable of representing epistasis and saturation effects. For a particular set of experiments, we derive the interaction matrix by minimizing a composite error function, aiming at accuracy of prediction and simplicity of network structure. To evaluate the predictive potential of the method, we performed 21 drug pair treatment experiments in a human breast cancer cell line (MCF7) with observation of phospho-proteins and cell cycle markers. The best derived network model rediscovered known interactions and contained interesting predictions. Possible applications include the discovery of regulatory interactions, the design of targeted combination therapies and the engineering of molecular biological networks. © 2008 EMBO and Macmillan Publishers Limited All rights reserved. |
| Keywords: | mitogen activated protein kinase; protein kinase b; s6 kinase; controlled study; human cell; raf protein; cancer combination chemotherapy; methodology; antineoplastic agent; accuracy; cell cycle protein; cell cycle; epidermal growth factor receptor; drug effect; cell line, tumor; breast neoplasms; phosphatidylinositol 3 kinase; mathematical model; models, theoretical; somatomedin c receptor; regulatory mechanism; quantitative analysis; breast tumor; cancer cell; mammalian target of rapamycin; tumor cell line; gefitinib; initiation factor 4e; phosphoproteins; molecular interaction; combination therapy; cell strain mcf 7; rapamycin; technique; model; phosphoprotein; theoretical model; 2 morpholino 8 phenylchromone; systems biology; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; protein kinase c delta; pharmaceutical preparations; drug; nonlinear system; bioengineering; synthetic biology; network dynamics; network pharmacology; rottlerin |
| Journal Title: | Molecular Systems Biology |
| Volume: | 4 |
| ISSN: | 1744-4292 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2008-01-01 |
| Start Page: | 216 |
| Language: | English |
| DOI: | 10.1038/msb.2008.53 |
| PUBMED: | 18766176 |
| PROVIDER: | scopus |
| PMCID: | PMC2564730 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 39" - "Export Date: 17 November 2011" - "Source: Scopus" |
Altmetric
Citation Impact
Related MSK Work