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BIOMD0000000424 - Faratian2009 - Role of PTEN in Trastuzumab resistance

 

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Reference Publication
Publication ID: 19638581
Faratian D, Goltsov A, Lebedeva G, Sorokin A, Moodie S, Mullen P, Kay C, Um IH, Langdon S, Goryanin I, Harrison DJ.
Systems biology reveals new strategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab.
Cancer Res. 2009 Aug; 69(16): 6713-6720
University of Edinburgh, Scotland, United Kingdom. d.faratian@ed.ac.uk  [more]
Model
Original Model: BIOMD0000000424.origin
Submitter: Galina Lebedeva
Submission ID: MODEL1108180000
Submission Date: 18 Aug 2011 13:13:07 UTC
Last Modification Date: 09 Oct 2014 18:39:47 UTC
Creation Date: 18 Aug 2011 13:13:07 UTC
Encoders:  Vijayalakshmi Chelliah
   Stuart Moodie
set #1
bqbiol:hasProperty Human Disease Ontology DOID:162
set #2
bqbiol:hasProperty Mathematical Modelling Ontology MAMO_0000046
set #3
bqbiol:hasTaxon Taxonomy Homo sapiens
set #4
bqbiol:occursIn Brenda Tissue Ontology breast cancer cell line
set #5
bqmodel:isDerivedFrom BioModels Database Kholodenko1999 - EGFR signaling
BioModels Database Hatakeyama2003_MAPK
set #6
bqbiol:isVersionOf Gene Ontology response to drug
Gene Ontology phosphatidylinositol 3-kinase signaling
Notes
Faratian2009 - Role of PTEN in Trastuzumab resistance

This model is described in the article:

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 Aug; 69(16): 6713-6720

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.

Model
Publication ID: 19638581 Submission Date: 18 Aug 2011 13:13:07 UTC Last Modification Date: 09 Oct 2014 18:39:47 UTC Creation Date: 18 Aug 2011 13:13:07 UTC
Mathematical expressions
Reactions
R1 R2 R3 R4
R5 R6 R7 R8
R9 R10 R11 R12
R13 R14 R15 R16_1
R16_2 R16_3 R17_1 R18_1
R18_2 R18_3 R19 R20
R21 R22 R23 R24
R25 R26 R27_1 R28_1
R28_2 R28_3 R28_4 R28_5
R28_6 R28_7 R29 R30
R31_1 R31_2 R31_3 R32
R33_1 R33_2 R33_3 R34
R35 R36 R37 R38
R39 R40 R41 R42
R43 R44    
Rules
Assignment Rule (variable: tE3P) Assignment Rule (variable: tPTEN) Assignment Rule (variable: tPTENP) Assignment Rule (variable: pAkt)
Assignment Rule (variable: tERKP)      
Physical entities
Compartments Species
Default E3 PI3K_LY E3H
E2 E23H E23HP
Shc E23HP_Shc E23HP_ShcP
GS E23HP_ShGS E2_Per
PTEN_bpV RasGDP PI3Ka_PIP3
Raf E23H_C MEK
MEKP PP2A MEKP_PP2A
MEK_PP2A Akt_PIP3_PP2A MEKPP_PP2A
ERK ERKP E3H_C
PI3K E23HP_PI3K Akt_PIP3
PI3Ka PI2 Akt_PI_P_PP2A
PTEN PIP3 PTEN_PIP3
PTEN_PI PTENP PTENP_PTEN
Akt_PI_P Akt E23HP_PI3Ka
PTEN_PTEN PI3Ka_PI MEKPP
Akt_PI_PP Akt_PI_PP_PP2A Per
ShGS E2Per ERKPP
Rafa RasGTP ShcP
HRG    
Global parameters
mu scal scall scalll
tE3P_max tERKP_max pAkt_max E3_0
PI0 Akt0 bpV LY
PI3K_CY k1 Kd_1 k2
Kd_2 k51 k53 k3
Kd_3 V4 K4 k5
Kd_5 k6 k_6 k7
Kd_7 k8 Kd_8 k9
k_9 V10 K10 k27
Kd_27 k28 k_28 k29
k_29 V30 k11 K11
V12 K12 k13 K13
k14 K14 E_raf k15
K15 k16 Kd_16 k16_kat
k18 k22 k23 K23
V24 K24 k31 K_d31
k55 k56 k32 Kd_32
k33 k34 V35 K35
k36 Kd_36 k37 k38
k39 Kd_39 V40 K40
k41 Kd_41 k42 k43
k47 k48 k49 Kd_49
k50 k_50 k57 Kd_57
k58 Kd_58 tPTEN sens
pAkt tE3P tERKP tPTENP
Pool_1_ Pool_2_ Pool_3_ Pool_4_
Pool_5_ Pool_6_ Pool_7_ Pool_8_
Pool_9_ Pool_10_ Pool_11_ Pool_12_
Pool_13_ Pool_14_    
Reactions (58)
 
 R1 [E3] + [HRG] → [E3H];  
 
 R2 [E2] + [E3H] → [E23H];  
 
 R3 [E23H] → [E23HP];  
 
 R4 [E23HP] → [E23H];  
 
 R5 [E23HP] + [Shc] → [E23HP_Shc];  
 
 R6 [E23HP_Shc] → [E23HP_ShcP];  
 
 R7 [E23HP_ShcP] + [GS] → [E23HP_ShGS];  
 
 R8 [E23HP_ShGS] → [E23HP] + [ShGS];  
 
 R9 [ShGS] → [GS] + [ShcP];  
 
 R10 [ShcP] → [Shc];  
 
 R11 [RasGDP] → [RasGTP];   {ShGS}
 
 R12 [RasGTP] → [RasGDP];  
 
 R13 [Raf] → [Rafa];   {RasGTP}
 
 R14 [Rafa] → [Raf];   {Akt_PI_PP}
 
 R15 [MEK] → [MEKP];   {Rafa}
 
 R16_1 [MEKP] + [PP2A] → [MEKP_PP2A];  
 
 R16_2 [MEKP_PP2A] → [MEK_PP2A];  
 
 R16_3 [MEK_PP2A] → [MEK] + [PP2A];  
 
 R17_1 [MEKP] → [MEKPP];   {Rafa}
 
 R18_1 [MEKPP] + [PP2A] → [MEKPP_PP2A];  
 
 R18_2 [MEKPP_PP2A] → [MEKP_PP2A];  
 
 R18_3 [MEKP_PP2A] → [MEKP] + [PP2A];  
 
 R19 [ERK] → [ERKP];   {MEKPP}
 
 R20 [ERKP] → [ERK];  
 
 R21 [ERKP] → [ERKPP];   {MEKPP}
 
 R22 [ERKPP] → [ERKP];  
 
 R23 [E23HP] + [PI3K] → [E23HP_PI3K];  
 
 R24 [E23HP_PI3K] → [E23HP_PI3Ka];  
 
 R25 [E23HP_PI3Ka] → [E23HP] + [PI3Ka];  
 
 R26 [PI3Ka] → [PI3K];  
 
 R27_1 [PI2] + [PI3Ka] → [PI3Ka_PI];  
 
 R28_1 [PIP3] + [PTEN] → [PTEN_PIP3];  
 
 R28_2 [PTEN_PIP3] → [PTEN_PI];  
 
 R28_3 [PTEN_PI] → [PI2] + [PTEN];  
 
 R28_4 [PTEN] → [PTENP];  
 
 R28_5 [PTEN] + [PTENP] → [PTENP_PTEN];  
 
 R28_6 [PTENP_PTEN] → [PTEN_PTEN];  
 
 R28_7 [PTEN_PTEN] → 2.0 × [PTEN];  
 
 R29 [Akt] + [PIP3] → [Akt_PIP3];  
 
 R30 [Akt_PIP3] → [Akt_PI_P];  
 
 R31_1 [Akt_PI_P] + [PP2A] → [Akt_PI_P_PP2A];  
 
 R31_2 [Akt_PI_P_PP2A] → [Akt_PIP3_PP2A];  
 
 R31_3 [Akt_PIP3_PP2A] → [Akt_PIP3] + [PP2A];  
 
 R32 [Akt_PI_P] → [Akt_PI_PP];  
 
 R33_1 [Akt_PI_PP] + [PP2A] → [Akt_PI_PP_PP2A];  
 
 R33_2 [Akt_PI_PP_PP2A] → [Akt_PI_P_PP2A];  
 
 R33_3 [Akt_PI_P_PP2A] → [Akt_PI_P] + [PP2A];  
 
 R34 [E23HP] → ;  
 
 R35 [E2] + [Per] → [E2_Per];  
 
 R36 [E2_Per] → [E2Per];  
 
 R37 [E3H] → [E3H_C];  
 
 R38 [E2] + [E3H_C] → [E23H];  
 
 R39 [E23H] → [E23H_C];  
 
 R40 [E23H_C] → [E23HP];  
 
 R41 [PI3Ka_PI] → [PI3Ka_PIP3];  
 
 R42 [PI3Ka_PIP3] → [PI3Ka] + [PIP3];  
 
 R43 [PTEN] → [PTEN_bpV];  
 
 R44 [PI3K] → [PI3K_LY];  
 
Rules (5)
 
 Assignment Rule (name: tE3P) tE3P = (E23HP+E23HP_PI3K+E23HP_PI3Ka+E23HP_Shc+E23HP_ShcP+E23HP_ShGS)/tE3P_max
 
 Assignment Rule (name: tPTEN) tPTEN = PTENP+PTEN+PTENP_PTEN+PTEN_PTEN+PTEN_PIP3+PTEN_PI
 
 Assignment Rule (name: tPTENP) tPTENP = PTENP/7.6
 
 Assignment Rule (name: pAkt) pAkt = (Akt_PI_PP+Akt_PI_P+Akt_PI_PP_PP2A+Akt_PI_P_PP2A)/pAkt_max
 
 Assignment Rule (name: tERKP) tERKP = (ERKP+ERKPP)/tERKP_max
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 E3
Compartment: Default
Initial concentration: 80.0
 
 PI3K_LY
Compartment: Default
Initial concentration: 0.0
 
 E3H
Compartment: Default
Initial concentration: 0.0
 
 E2
Compartment: Default
Initial concentration: 100.0
 
 E23H
Compartment: Default
Initial concentration: 0.0
 
 E23HP
Compartment: Default
Initial concentration: 0.0
 
 Shc
Compartment: Default
Initial concentration: 100.0
 
 E23HP_Shc
Compartment: Default
Initial concentration: 0.0
 
 E23HP_ShcP
Compartment: Default
Initial concentration: 0.0
 
 GS
Compartment: Default
Initial concentration: 100.0
 
 E23HP_ShGS
Compartment: Default
Initial concentration: 0.0
 
 E2_Per
Compartment: Default
Initial concentration: 0.0
 
 PTEN_bpV
Compartment: Default
Initial concentration: 0.0
 
 RasGDP
Compartment: Default
Initial concentration: 120.0
 
 PI3Ka_PIP3
Compartment: Default
Initial concentration: 0.0
 
 Raf
Compartment: Default
Initial concentration: 100.0
 
 E23H_C
Compartment: Default
Initial concentration: 0.0
 
 MEK
Compartment: Default
Initial concentration: 10.0
 
 MEKP
Compartment: Default
Initial concentration: 0.0
 
 PP2A
Compartment: Default
Initial concentration: 10.0
 
 MEKP_PP2A
Compartment: Default
Initial concentration: 0.0
 
 MEK_PP2A
Compartment: Default
Initial concentration: 0.0
 
 Akt_PIP3_PP2A
Compartment: Default
Initial concentration: 0.0
 
 MEKPP_PP2A
Compartment: Default
Initial concentration: 0.0
 
 ERK
Compartment: Default
Initial concentration: 10.0
 
 ERKP
Compartment: Default
Initial concentration: 0.0
 
 E3H_C
Compartment: Default
Initial concentration: 0.0
 
 PI3K
Compartment: Default
Initial concentration: 200.0
 
 E23HP_PI3K
Compartment: Default
Initial concentration: 0.0
 
 Akt_PIP3
Compartment: Default
Initial concentration: 0.0
 
 PI3Ka
Compartment: Default
Initial concentration: 0.0
 
 PI2
Compartment: Default
Initial concentration: 300.0
 
 Akt_PI_P_PP2A
Compartment: Default
Initial concentration: 0.0
 
 PTEN
Compartment: Default
Initial concentration: 42.7798
 
 PIP3
Compartment: Default
Initial concentration: 8.05772E-12
 
 PTEN_PIP3
Compartment: Default
Initial concentration: 3.14554E-8
 
 PTEN_PI
Compartment: Default
Initial concentration: 5.02914E-8
 
 PTENP
Compartment: Default
Initial concentration: 3.39885
 
 PTENP_PTEN
Compartment: Default
Initial concentration: 0.955337
 
 Akt_PI_P
Compartment: Default
Initial concentration: 0.0
 
 Akt
Compartment: Default
Initial concentration: 100.0
 
 E23HP_PI3Ka
Compartment: Default
Initial concentration: 0.0
 
 PTEN_PTEN
Compartment: Default
Initial concentration: 0.955337
 
 PI3Ka_PI
Compartment: Default
Initial concentration: 0.0
 
 MEKPP
Compartment: Default
Initial concentration: 0.0
 
 Akt_PI_PP
Compartment: Default
Initial concentration: 0.0
 
 Akt_PI_PP_PP2A
Compartment: Default
Initial concentration: 0.0
 
 Per
Compartment: Default
Initial concentration: 0.0
 
 ShGS
Compartment: Default
Initial concentration: 0.0
 
 E2Per
Compartment: Default
Initial concentration: 0.0
 
 ERKPP
Compartment: Default
Initial concentration: 0.0
 
 Rafa
Compartment: Default
Initial concentration: 0.0
 
 RasGTP
Compartment: Default
Initial concentration: 0.0
 
 ShcP
Compartment: Default
Initial concentration: 0.0
 
 HRG
Compartment: Default
Initial concentration: 3000.0
 
Global Parameters (114)
 
   mu  
 
   scal
Value: 1.0
 
   scall
Value: 0.6
 
   scalll
Value: 30.0
 
   tE3P_max
Value: 65.0
 
   tERKP_max
Value: 10.0
 
   pAkt_max
Value: 91.0
 
   E3_0  
 
   PI0
Value: 70.0
 
   Akt0
Value: 10.0
 
   bpV  
 
   LY  
 
   PI3K_CY  
 
   k1
Value: 0.005
 
   Kd_1
Value: 600.0
 
   k2
Value: 10.0
 
   Kd_2
Value: 10.0
 
   k51
Value: 0.01
 
   k53
Value: 0.01
 
   k3
Value: 1.0
 
   Kd_3
Value: 0.1
 
   V4
Value: 10.0
 
   K4
Value: 50.0
 
   k5
Value: 0.06
 
   Kd_5
Value: 1.0
 
   k6
Value: 12.0
 
   k_6
Value: 3.0
 
   k7
Value: 36.0
 
   Kd_7
Value: 9.0
 
   k8
Value: 12.0
 
   Kd_8
Value: 0.1
 
   k9
Value: 35.0
 
   k_9  
 
   V10
Value: 0.0154
 
   K10
Value: 340.0
 
   k27
Value: 3.0
 
   Kd_27
Value: 1.0
 
   k28
Value: 300.0
 
   k_28  
 
   k29
Value: 13520.0
 
   k_29  
 
   V30
Value: 900.0
 
   k11
Value: 6.0
 
   K11
Value: 0.18
 
   V12
Value: 3.0
 
   K12
Value: 0.1
 
   k13
Value: 1.0
 
   K13
Value: 11.7
 
   k14
Value: 0.6
 
   K14
Value: 50.0
 
   E_raf
Value: 7.0
 
   k15
Value: 2.1
 
   K15
Value: 1.0
 
   k16
Value: 0.06
 
   Kd_16
Value: 1.0
 
   k16_kat
Value: 0.6
 
   k18
Value: 0.6
 
   k22
Value: 0.06
 
   k23
Value: 1.2
 
   K23
Value: 10.0
 
   V24
Value: 1.8
 
   K24
Value: 10.0
 
   k31
Value: 0.03
 
   K_d31
Value: 100.0
 
   k55
Value: 30.0
 
   k56
Value: 30.0
 
   k32
Value: 8000.0
 
   Kd_32
Value: 0.01
 
   k33
Value: 15.0
 
   k34
Value: 3.6
 
   V35
Value: 150.0
 
   K35
Value: 2.0
 
   k36
Value: 1.0
 
   Kd_36
Value: 2.2
 
   k37
Value: 150.0
 
   k38
Value: 150.0
 
   k39
Value: 15000.0
 
   Kd_39
Value: 20.0
 
   V40
Value: 15000.0
 
   K40
Value: 0.1
 
   k41
Value: 3.0
 
   Kd_41
Value: 0.1
 
   k42
Value: 45.0
 
   k43
Value: 30.0
 
   k47
Value: 0.3
 
   k48
Value: 0.001
 
   k49
Value: 0.003
 
   Kd_49
Value: 20000.0
 
   k50
Value: 0.6
 
   k_50
Value: 0.012
 
   k57
Value: 100.0
 
   Kd_57
Value: 10.0
 
   k58
Value: 100.0
 
   Kd_58
Value: 80.0
 
   tPTEN  
 
   sens  
 
   pAkt  
 
   tE3P  
 
   tERKP  
 
   tPTENP  
 
   Pool_1_
Value: 2900.0
 
   Pool_2_
Value: -2920.0
 
   Pool_3_
Value: 200.0
 
   Pool_4_
Value: 50.0
 
   Pool_5_
Value: 300.0
 
   Pool_6_  
 
   Pool_7_
Value: 10.0
 
   Pool_8_
Value: 100.0
 
   Pool_9_
Value: 10.0
 
   Pool_10_
Value: 10.0
 
   Pool_11_
Value: 100.0
 
   Pool_12_
Value: 120.0
 
   Pool_13_
Value: 100.0
 
   Pool_14_
Value: 100.0
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000424

Curator's comment: (updated: 01 Aug 2012 14:47:16 GMT)

The model reproduces Figure S4 of the reference publication, that correspond to the effect of heregulin-beta (black). In order to reproduce the plot that correspond to the effect of pertuzumab (blue), the initial concentration of Per should be set as 300000. For more details about the scaling factor used in the concentration of Per, look in the notes of the "Per".

The data were obtained by simulation the model using Copasi v4.8 (Build 35). The plots were made using Gnuplot.

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