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BIOMD0000000427 - Bianconi2012 - EGFR and IGF1R pathway in lung cancer

 

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Reference Publication
Publication ID: 21620944
Bianconi F, Baldelli E, Ludovini V, Crinò L, Flacco A, Valigi P.
Computational model of EGFR and IGF1R pathways in lung cancer: a Systems Biology approach for Translational Oncology.
Biotechnol. Adv. 2012 Jan-Feb; 30(1): 142-153
Department of Electronic and Information Engineering, Perugia University, Italy. fortunato.bianconi@diei.unipg.it  [more]
Model
Original Model: http://sourceforge.net/pro...
Submitter: Fortunato Bianconi
Submission ID: MODEL1209230000
Submission Date: 23 Sep 2012 10:34:38 UTC
Last Modification Date: 23 May 2017 10:30:00 UTC
Creation Date: 20 Nov 2012 18:31:02 UTC
Encoders:  Vijayalakshmi Chelliah
   Fortunato Bianconi
set #1
bqbiol:isVersionOf Gene Ontology regulation of phosphatidylinositol 3-kinase signaling
Gene Ontology regulation of ERK1 and ERK2 cascade
set #2
bqbiol:hasVersion Human Disease Ontology non-small cell lung carcinoma
set #3
bqbiol:isPartOf Gene Ontology epidermal growth factor receptor signaling pathway
Gene Ontology insulin-like growth factor receptor signaling pathway
Pathway Ontology lung cancer pathway
bqbiol:hasTaxon Taxonomy Homo sapiens
set #4
bqbiol:hasProperty Mathematical Modelling Ontology MAMO_0000046
Notes
Bianconi2012 - EGFR and IGF1R pathway in lung cancer

EGFR and IGF1R pathways play a key role in various human cancers and are crucial for tumour transformation and survival of malignant cells. High EGFR and IGF1R expression and activity has been associated with multiple aspects of cancer progression including tumourigenesis, metastasis, resistance to chemotherapeutics and other molecularly targeted drugs. Here, the biological relationship between the proteins involved in EGFR and IGF1R pathways and the downstream MAPK and PIK3 networks has been modelled to study the time behaviour of the overall system, and the functional interdependencies among the receptors, the proteins and kinases involved.

This model is described in the article:

Bianconi F, Baldelli E, Ludovini V, Crinò L, Flacco A, Valigi P.
Biotechnol Adv. 2012 Jan-Feb;30(1):142-53.

Abstract:

In this paper we propose a Systems Biology approach to understand the molecular biology of the Epidermal Growth Factor Receptor (EGFR, also known as ErbB1/HER1) and type 1 Insulin-like Growth Factor (IGF1R) pathways in non-small cell lung cancer (NSCLC). This approach, combined with Translational Oncology methodologies, is used to address the experimental evidence of a close relationship among EGFR and IGF1R protein expression, by immunohistochemistry (IHC) and gene amplification, by in situ hybridization (FISH) and the corresponding ability to develop a more aggressive behavior. We develop a detailed in silico model, based on ordinary differential equations, of the pathways and study the dynamic implications of receptor alterations on the time behavior of the MAPK cascade down to ERK, which in turn governs proliferation and cell migration. In addition, an extensive sensitivity analysis of the proposed model is carried out and a simplified model is proposed which allows us to infer a similar relationship among EGFR and IGF1R activities and disease outcome.

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.

Model
Publication ID: 21620944 Submission Date: 23 Sep 2012 10:34:38 UTC Last Modification Date: 23 May 2017 10:30:00 UTC Creation Date: 20 Nov 2012 18:31:02 UTC
Mathematical expressions
Reactions
SOS conformational activation kRas Activation EGFR degradation ERK activation by Mek
SOS deactivation by P90 SOS activation by IGF PI3KCA activation by IGF1R PI3KCA activation by EGF
Akt activation by PI3KCA Akt deactivation ERK deactivation by PP2A PI3KCA activation by kRas
Raf activation by kRas Mek activation by Raf Raf deactivation by Akt Ras deactivation by RasGab
Mek deactivation by PP2A IGFR active degradation PI3KCA deactivation Raf deactivation by RafPP
P90 activation by ERK P90 deactivation    
Physical entities
Compartments Species
cell_nsclc EGFR_active D_SOS A_SOS
Raf Ras_active Mek_active
ERK ERK_active IGFR_active
PI3KCA PI3KCA_active AKT_active
AKT PP2A Ras
Raf_active Mek RasGapActive
RafPP P90RskInactive P90Rsk_Active
Global parameters
gamma_IGFR kd_PI3K_a k_P90Rsk_ERKActive KM_P90Rsk_ERKActive
gamma_EGFR      
Reactions (22)
 
 SOS conformational activation [D_SOS] + [EGFR_active] → [A_SOS] + [EGFR_active];   {EGFR_active} , {D_SOS}
 
 kRas Activation [A_SOS] + [Ras] → [Ras_active] + [A_SOS];   {A_SOS} , {Ras}
 
 EGFR degradation [EGFR_active] → ;   {EGFR_active}
 
 ERK activation by Mek [ERK] + [Mek_active] → [ERK_active] + [Mek_active];   {Mek_active} , {ERK}
 
 SOS deactivation by P90 [P90Rsk_Active] + [A_SOS] → [D_SOS] + [P90Rsk_Active];   {P90Rsk_Active} , {A_SOS}
 
 SOS activation by IGF [IGFR_active] + [D_SOS] → [A_SOS] + [IGFR_active];   {IGFR_active} , {D_SOS}
 
 PI3KCA activation by IGF1R [PI3KCA] + [IGFR_active] → [PI3KCA_active] + [IGFR_active];   {IGFR_active} , {PI3KCA}
 
 PI3KCA activation by EGF [PI3KCA] + [EGFR_active] → [PI3KCA_active] + [EGFR_active];   {EGFR_active} , {PI3KCA}
 
 Akt activation by PI3KCA [AKT] + [PI3KCA_active] → [AKT_active] + [PI3KCA_active];   {PI3KCA_active} , {AKT}
 
 Akt deactivation [AKT_active] → [AKT];   {AKT_active}
 
 ERK deactivation by PP2A [ERK_active] + [PP2A] → [ERK] + [PP2A];   {PP2A} , {ERK_active}
 
 PI3KCA activation by kRas [PI3KCA] + [Ras_active] → [PI3KCA_active] + [Ras_active];   {Ras_active} , {PI3KCA}
 
 Raf activation by kRas [Ras_active] + [Raf] → [Raf_active] + [Ras_active];   {Ras_active} , {Raf}
 
 Mek activation by Raf [Raf_active] + [Mek] → [Mek_active] + [Raf_active];   {Raf_active} , {Mek}
 
 Raf deactivation by Akt [AKT_active] + [Raf_active] → [Raf] + [AKT_active];   {AKT_active} , {Raf_active}
 
 Ras deactivation by RasGab [RasGapActive] + [Ras_active] → [Ras] + [RasGapActive];   {RasGapActive} , {Ras_active}
 
 Mek deactivation by PP2A [PP2A] + [Mek_active] → [Mek] + [PP2A];   {PP2A} , {Mek_active}
 
 IGFR active degradation [IGFR_active] → ;   {IGFR_active}
 
 PI3KCA deactivation [PI3KCA_active] → [PI3KCA];   {PI3KCA_active}
 
 Raf deactivation by RafPP [RafPP] + [Raf_active] → [Raf] + [RafPP];   {RafPP} , {Raf_active}
 
 P90 activation by ERK [P90RskInactive] + [ERK_active] → [P90Rsk_Active] + [ERK_active];   {ERK_active} , {P90RskInactive}
 
 P90 deactivation [P90Rsk_Active] → [P90RskInactive];   {P90Rsk_Active}
 
 cell_nsclc Spatial dimensions: 3.0  Compartment size: 1.0
 
 EGFR_active
Compartment: cell_nsclc
Initial amount: 8000.0
 
 D_SOS
Compartment: cell_nsclc
Initial amount: 120000.0
 
 A_SOS
Compartment: cell_nsclc
Initial amount: 0.0
 
 Raf
Compartment: cell_nsclc
Initial amount: 120000.0
 
 Ras_active
Compartment: cell_nsclc
Initial amount: 0.0
 
 Mek_active
Compartment: cell_nsclc
Initial amount: 0.0
 
 ERK
Compartment: cell_nsclc
Initial amount: 600000.0
 
 ERK_active
Compartment: cell_nsclc
Initial amount: 0.0
 
 IGFR_active
Compartment: cell_nsclc
Initial amount: 800.0
 
 PI3KCA
Compartment: cell_nsclc
Initial amount: 120000.0
 
 PI3KCA_active
Compartment: cell_nsclc
Initial amount: 0.0
 
 AKT_active
Compartment: cell_nsclc
Initial amount: 0.0
 
 AKT
Compartment: cell_nsclc
Initial amount: 600000.0
 
 PP2A
Compartment: cell_nsclc
Initial amount: 120000.0
 
 Ras
Compartment: cell_nsclc
Initial amount: 120000.0
 
 Raf_active
Compartment: cell_nsclc
Initial amount: 0.0
 
 Mek
Compartment: cell_nsclc
Initial amount: 600000.0
 
 RasGapActive
Compartment: cell_nsclc
Initial amount: 120000.0
 
 RafPP
Compartment: cell_nsclc
Initial amount: 120000.0
 
 P90RskInactive
Compartment: cell_nsclc
Initial amount: 120000.0
 
 P90Rsk_Active
Compartment: cell_nsclc
Initial amount: 0.0
 
Global Parameters (5)
 
   gamma_IGFR
Value: 0.02
Constant
 
   kd_PI3K_a
Value: 0.005
Constant
 
   k_P90Rsk_ERKActive
Value: 0.0213697
Constant
 
   KM_P90Rsk_ERKActive
Value: 763523.0
Constant
 
   gamma_EGFR
Value: 0.02
Constant
 
SOS conformational activation (3)
 
   k_SOS_E
Value: 694.731
Constant
 
   n_SOS
Value: 1.0
Constant
 
   KM_SOS_E
Value: 6086070.0
Constant
 
kRas Activation (3)
 
   k_Ras_SOS
Value: 32.344
Constant
 
   n_Ras_SOS
Value: 1.0
Constant
 
   KM_Ras_SOS
Value: 35954.3
Constant
 
ERK activation by Mek (2)
 
   k_ERK_MekActive
Value: 9.85367
Constant
 
   KM_ERK_MekActive
Value: 1007340.0
Constant
 
SOS deactivation by P90 (3)
 
   k_D_SOS_P90Rsk
Value: 161197.0
Constant
 
   n_D_SOS
Value: 1.0
Constant
 
   KM_D_SOS_P90Rsk
Value: 896896.0
Constant
 
SOS activation by IGF (3)
 
   k_A_SOS_I
Value: 500.0
Constant
 
   n_A_SOS_I
Value: 1.0
Constant
 
   KM_A_SOS_I
Value: 100000.0
Constant
 
PI3KCA activation by IGF1R (3)
 
   k_PI3K_IGF1R
Value: 10.6737
Constant
 
   n_PI3K_I
Value: 1.0
Constant
 
   KM_PI3K_IGF1R
Value: 184912.0
Constant
 
PI3KCA activation by EGF (3)
 
   k_PI3K_EGF1R
Value: 10.6737
Constant
 
   n_PI3K_E
Value: 1.0
Constant
 
   KM_PI3K_EGF1R
Value: 184912.0
Constant
 
Akt activation by PI3KCA (3)
 
   k_AKT_PI3K
Value: 0.0566279
Constant
 
   n_AKT_PI3K
Value: 1.0
Constant
 
   KM_AKT_PI3K
Value: 653951.0
Constant
 
Akt deactivation (1)
 
   kd_AKT
Value: 0.005
Constant
 
ERK deactivation by PP2A (3)
 
   k_ERKactive_PP2A
Value: 8.8912
Constant
 
   n_ERKactive_PP2A
Value: 1.0
Constant
 
   KM_ERKactive_PP2A
Value: 3496490.0
Constant
 
PI3KCA activation by kRas (3)
 
   k_PI3K_Ras
Value: 0.0771067
Constant
 
   n_PI3K_Ras
Value: 1.0
Constant
 
   KM_PI3K_Ras
Value: 272056.0
Constant
 
Raf activation by kRas (3)
 
   k_Raf_RasActive
Value: 0.884096
Constant
 
   n_Raf_RasActive
Value: 1.0
Constant
 
   KM_Raf_RasActive
Value: 62464.6
Constant
 
Mek activation by Raf (3)
 
   k_Mek_PP2A
Value: 185.759
Constant
 
   n_Mek_PP2A
Value: 1.0
Constant
 
   KM_MekPP2A
Value: 4768350.0
Constant
 
Raf deactivation by Akt (3)
 
   k_Raf_AKT
Value: 15.1212
Constant
 
   n_Raf_AKT
Value: 1.0
Constant
 
   KM_Raf_AKT
Value: 119355.0
Constant
 
Ras deactivation by RasGab (3)
 
   k_RasActiveRasGap
Value: 1509.36
Constant
 
   n_RasActiveRasGap
Value: 1.0
Constant
 
   KM_RasActiveRasGap
Value: 1432410.0
Constant
 
Mek deactivation by PP2A (3)
 
   k_MekActivePP2A
Value: 2.83243
Constant
 
   n_MekActivePP2A
Value: 1.0
Constant
 
   KM_MekActivePP2A
Value: 518753.0
Constant
 
Raf deactivation by RafPP (3)
 
   k_RasActive_RafPP
Value: 0.126329
Constant
 
   n_RasActive_RafPP
Value: 1.0
Constant
 
   KM_RasActive_RafPP
Value: 1061.71
Constant
 
P90 deactivation (1)
 
   kd_P90Rsk
Value: 0.005
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000427

Curator's comment: (updated: 19 Nov 2012 13:24:06 GMT)

The model reproduce figure 2a of the reference publication, by setting EGFR_active = 8000 and IGFR_active = 650.

The initial concentrations for reproducing figure 2b and 2c can be obtained from the matlab file of model, which accompanies the reference publication.

The model was simulated using Copasi v4.8 (Build 35). The plot was generated using Gnuplot.

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