This model is from the article: Systems biology reveals new strategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab. Faratian D, Goltsov A, Lebedeva G, Sorokin A, Moodie S, Mullen P, Kay C, Um IH, Langdon S, Goryanin I, Harrison DJ Cancer Res. 2009; 69(16): 6713-20 19638581 , Abstract: Resistance to targeted cancer therapies such as trastuzumab is a frequent clinical problem not solely because of insufficient expression of HER2 receptor but also because of the overriding activation states of cell signaling pathways. Systems biology approaches lend themselves to rapid in silico testing of factors, which may confer resistance to targeted therapies. Inthis study, we aimed to develop a new kinetic model that could be interrogated to predict resistance to receptor tyrosine kinase (RTK) inhibitor therapies and directly test predictions in vitro and in clinical samples. The new mathematical model included RTK inhibitor antibody binding, HER2/HER3 dimerization and inhibition, AKT/mitogen-activated protein kinase cross-talk, and the regulatory properties of PTEN. The model was parameterized using quantitative phosphoprotein expression data from cancer cell lines using reverse-phase protein microarrays. Quantitative PTEN protein expression was found to be the key determinant of resistance to anti-HER2 therapy in silico, which was predictive of unseen experiments in vitro using the PTEN inhibitor bp(V). When measured in cancer cell lines, PTEN expression predicts sensitivity to anti-HER2 therapy; furthermore, this quantitative measurement is more predictive of response (relative risk, 3.0; 95% confidence interval, 1.6-5.5; P < 0.0001) than other pathway components taken in isolation and when tested by multivariate analysis in a cohort of 122 breast cancers treated with trastuzumab. For the first time, a systems biology approach has successfully been used to stratify patients for personalized therapy in cancer and is further compelling evidence that PTEN, appropriately measured in the clinical setting, refines clinical decision making in patients treated with anti-HER2 therapies. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
Kinetic equations are usually written in terms of concentrations (not of mole numbers), since the reaction rates are functions of concentrations. If the same compound participates in reactions taking place in different compartments with different volumes, the effective concentration of that compound will be different depending on the volume of the corresponding compartment. Step 1 (EGF binding to EGFR) could be considered as taking place in the extracellular compartment with a given initial concentration of EGF. The concentration of EGFR in the extracellular compartment would then be calculated as the number of the receptors on the cell surface divided by the (average) volume of incubation medium per cell (V m). In step 2, association and dissociation of the receptor monomers occurs in the cell membrane. All other steps are considered as taking place in the cytosolic compartment. Therefore, the same mole number of EGFR would give rise to three EGFR concentrations (representing the different compartments). However, for computational purposes, it is more convenient to deal only with a single concentration of EGFR related to the cytoplasmic water volume (V cw) of the cell. This requires rescaling the rate constants of steps 1 and 2. For the purpose of this rescaling, the EGF concentration in the model was also related to the cytoplasmic water volume; i.e. [EGF] in the experimental medium was multiplied by the ratio Vm/V cw (see TableII). Typically, there were 107cells/ml in our experiments (see “Cell Preparation and Incubation Conditions”); therefore, Vm = 10−7 ml. Assuming the diameter of a hepatocyte of 20 μm and a cytoplasmic water volume of about 70% of total intracellular volume, Vm/Vcw = 33.3. [taken from Kholodenko 1999; http://www.jbc.org/content/274/42/30169.long] Per = 0 [without Inhibitor Pertuzumab] Per = 300000 [with Inhibitor Pertuzumab] - Stuart Moodie