Ito2019 - gefitnib resistance of lung adenocarcinoma caused by MET amplification
View the 2021-03 Model of the Month entry for this model
Model Identifier
BIOMD0000000827
Short description
The model is based on publication:
Mathematical analysis of gefitinib resistance of lung adenocarcinoma caused by MET amplification
Abstract:
Gefitinib, one of the tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR), is effective for treating lung adenocarcinoma harboring EGFR mutation; but later, most cases acquire a resistance to gefitinib. One of the mechanisms conferring gefitinib resistance to lung adenocarcinoma is the amplification of the MET gene, which is observed in 5–22% of gefitinib-resistant tumors. A previous study suggested that MET amplification could cause gefitinib resistance by driving ErbB3-dependent activation of the PI3K pathway. In this study, we built a mathematical model of gefitinib resistance caused by MET amplification using lung adenocarcinoma HCC827-GR (gefitinib resistant) cells. The molecular reactions involved in gefitinib resistance consisted of dimerization and phosphorylation of three molecules, EGFR, ErbB3, and MET were described by a series of ordinary differential equations. To perform a computer simulation, we quantified each molecule on the cell surface using flow cytometry and estimated unknown parameters by dimensional analysis. Our simulation showed that the number of active ErbB3 molecules is around a hundred-fold smaller than that of active MET molecules. Limited contribution of ErbB3 in gefitinib resistance by MET amplification is also demonstrated using HCC827-GR cells in culture experiments. Our mathematical model provides a quantitative understanding of the molecular reactions underlying drug resistance.
Format
SBML
(L2V4)
Related Publication
- Mathematical analysis of gefitinib resistance of lung adenocarcinoma caused by MET amplification.
- Ito T, Kumagai Y, Itano K, Maruyama T, Tamura K, Kawasaki S, Suzuki T, Murakami Y
- Biochemical and biophysical research communications , 4/ 2019 , Volume 511 , Issue 3 , pages: 544-550 , PubMed ID: 30824185
- Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
- Gefitinib, one of the tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR), is effective for treating lung adenocarcinoma harboring EGFR mutation; but later, most cases acquire a resistance to gefitinib. One of the mechanisms conferring gefitinib resistance to lung adenocarcinoma is the amplification of the MET gene, which is observed in 5-22% of gefitinib-resistant tumors. A previous study suggested that MET amplification could cause gefitinib resistance by driving ErbB3-dependent activation of the PI3K pathway. In this study, we built a mathematical model of gefitinib resistance caused by MET amplification using lung adenocarcinoma HCC827-GR (gefitinib resistant) cells. The molecular reactions involved in gefitinib resistance consisted of dimerization and phosphorylation of three molecules, EGFR, ErbB3, and MET were described by a series of ordinary differential equations. To perform a computer simulation, we quantified each molecule on the cell surface using flow cytometry and estimated unknown parameters by dimensional analysis. Our simulation showed that the number of active ErbB3 molecules is around a hundred-fold smaller than that of active MET molecules. Limited contribution of ErbB3 in gefitinib resistance by MET amplification is also demonstrated using HCC827-GR cells in culture experiments. Our mathematical model provides a quantitative understanding of the molecular reactions underlying drug resistance.
Contributors
Szeyi Ng
Metadata information
is
isDescribedBy
hasProperty
isPropertyOf
Mathematical Modelling Ontology
Ordinary differential equation model
Experimental Factor Ontology cancer
Experimental Factor Ontology cancer
Curation status
Curated
Modelling approach(es)
Tags
Name | Description | Size | Actions |
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Model files |
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Ito2019 - gefitnib resistance of lung adenocarcinoma caused by MET amplification.xml | SBML L2V4 file for the model | 55.84 KB | Preview | Download |
Additional files |
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Ito2019 - gefitnib resistance of lung adenocarcinoma caused by MET amplification.cps | COPASI 4.24 (Build 197) file for the model | 78.17 KB | Preview | Download |
Fig 3.png | PNG plot of the model simulation Figure 3 | 100.55 KB | Preview | Download |
- Model originally submitted by : Szeyi Ng
- Submitted: 30-Sep-2019 09:43:41
- Last Modified: 30-Sep-2019 09:43:41
Revisions
Legends
: Variable used inside SBML models
: Variable used inside SBML models
Species
Species | Initial Concentration/Amount |
---|---|
X 5 EGFR ErbB3 Combination ; CCO:1956; CCO:13867 |
0.0 mmol |
X 3 MET CCO:2065 |
7.4E-12 mmol |
X 1 EGFR CCO:1956 |
3.6E-12 mmol |
X 4 EGFR EGFR Combination ; CCO:1956 |
0.0 mmol |
X 2 ErbB3 CCO:13867 |
5.5E-14 mmol |
X 6 ErbB3 ErbB3 CCO:13867; Combination |
0.0 mmol |
X 7 MET MET Met-Met ; Combination |
0.0 mmol |
X 10 p MET MET Combination ; Met-Met |
0.0 mmol |
X 8 p EGFR ErbB3 CCO:13867; CCO:1956; Combination |
0.0 mmol |
X 9 p ErbB3 ErbB3 CCO:13867; Combination |
0.0 mmol |
Reactions
Reactions | Rate | Parameters |
---|---|---|
X_8_p_EGFR_ErbB3 => X_5_EGFR_ErbB3 | compartment*l_p2*X_8_p_EGFR_ErbB3 | l_p2 = 0.028 |
X_3_MET => X_7_MET_MET | compartment*(0.5*k_4*X_3_MET^2-l_4*X_7_MET_MET) | k_4 = 2.6E12; l_4 = 1.0 |
X_1_EGFR => X_4_EGFR_EGFR | compartment*(0.5*k_1*X_1_EGFR^2-l_1*X_4_EGFR_EGFR) | l_1 = 1.24; k_1 = 2.3E10 |
X_2_ErbB3 => X_6_ErbB3_ErbB3 | compartment*(0.5*k_2*X_2_ErbB3^2-l_2*X_6_ErbB3_ErbB3) | k_2 = 1.9E12; l_2 = 1.08 |
X_1_EGFR + X_2_ErbB3 => X_5_EGFR_ErbB3 | compartment*(k_3*X_1_EGFR*X_2_ErbB3-l_3*X_5_EGFR_ErbB3) | k_3 = 2.4E11; l_3 = 1.0 |
X_10_p_MET_MET + X_6_ErbB3_ErbB3 => X_10_p_MET_MET + X_9_p_ErbB3_ErbB3 | compartment*k_p3*X_6_ErbB3_ErbB3*X_10_p_MET_MET | k_p3 = 1.0E10 |
X_9_p_ErbB3_ErbB3 => X_6_ErbB3_ErbB3 | compartment*l_p3*X_9_p_ErbB3_ErbB3 | l_p3 = 0.028 |
X_7_MET_MET => X_10_p_MET_MET | compartment*(k_p1*X_7_MET_MET-l_p1*X_10_p_MET_MET) | k_p1 = 0.045; l_p1 = 0.028 |
X_10_p_MET_MET + X_5_EGFR_ErbB3 => X_10_p_MET_MET + X_8_p_EGFR_ErbB3 | compartment*k_p2*X_5_EGFR_ErbB3*X_10_p_MET_MET | k_p2 = 1.0E10 |
Curator's comment:
(added: 30 Sep 2019, 09:43:14, updated: 30 Sep 2019, 09:43:14)
(added: 30 Sep 2019, 09:43:14, updated: 30 Sep 2019, 09:43:14)
I reproduced Fig 3 from the publication. I generated the data using COPASI file and plot the figures using matlab.