#1 CODE

# a model to generate PKM2–KRAS signal–response curves

# initial conditions

init KRAS=0, PKM2=0

# differential equations

# KRAS represents the active form of KRAS

KRAS’= (karas + karas’*PKM2)*(KRAST-KRAS)/(Jkras + KRAST-KRAS)−(kiras + kiras’*VitC)*KRAS/(Jkras + KRAS)

# PKM2 represents the active form of PKM2

PKM2’ = (kapkm + kapkm’*KRAS + kapkm”*cMyc)*(PKM2T-PKM2)/(Jpkm + PKM2T-PKM2)−kipkm*PKM2/(Jpkm + PKM2)

# steady state functions

# mTOR represents the active form of mTOR

mTOR = mTORT*GK(kamr + kamr’*KRAS + kamr”*PKM2,kimr + kimr’*CHL,Jmr,Jmr)

# cMyc represents the active form of cMyc

cMyc = cMycT*GK(kamyc + kamyc’*PKM2 + kamyc”*mTOR,kimyc,Jmyc,Jmyc)

# ‘Goldbeter-Koshand’ function (GK)

GB(arg1,arg2,arg3,arg4) = arg2-arg1+arg2*arg3+arg1*arg4

GK(arg1,arg2,arg3,arg4) = 2*arg1*arg4/(GB(arg1,arg2,arg3,arg4)+sqrt(GB(arg1,arg2,arg3,arg4)^2-4*(arg2-arg1)*arg1*arg4))

# parameters

# to simulate cancer: karas=1

# to simulate chloroquine treatment in cancer: karas=1, kimr’=1.5

# to simulate Vitamin C treatment in cancer: karas=1, kiras’=1.5

# to simulate PKM2 over-expression: karas=0.01, kapkm=0.5

# to simulate PKM2 depletion: karas=0.01, PKM2T=0.01

# to simulate cMyc over-expression: karas=1, cMycT=10

# to simulate cMyc depletion: karas=1, cMycT=0.1

p karas=0.01, karas’=0.1, kiras=0.1, kiras’=0, KRAST=1, Jkras=0.1

p kamr=0.01, kamr’=0.1, kamr”=2.25, kimr=0.1, kimr’=0, mTORT=1, Jmr=0.1

p kapkm=0.05, kapkm’=0.1, kapkm”=0.2, kipkm=0.2, PKM2T=1, Jpkm=0.1

p kamyc=0.01, kamyc’=0.2, kamyc”=0.2, kimyc=0.3, cMycT=1, Jmyc=0.1

p CHL=1, VitC=1

done

#2 CODE

# a model to generate mTOR–KRAS signal–response curves

# initial conditions

init KRAS=0, PKM2=0

# differential equations

# mTOR represents the active form of mTOR

mTOR’ = (kamr + kamr’*KRAS + kamr”*PKM2)*(mTORT-mTOR)/(Jmr + mTORT-mTOR)−(kimr + kimr’*CHL)*mTOR/(Jmr + mTOR)

# PKM2 represents the active form of PKM2

PKM2’ = (kapkm + kapkm’*KRAS + kapkm”*cMyc)*(PKM2T-PKM2)/(Jpkm + PKM2T-PKM2)−kipkm*PKM2/(Jpkm + PKM2)

# steady state functions

# KRAS represents the active form of KRAS

KRAS = KRAST*GK(karas + karas’*PKM2,kiras + kiras’*VitC,Jkras,Jkras)

# cMyc represents the active form of cMyc

cMyc = cMycT*GK(kamyc + kamyc’*PKM2 + kamyc”*mTOR,kimyc,Jmyc,Jmyc)

# ‘Goldbeter-Koshand’ function (GK)

GB(arg1,arg2,arg3,arg4) = arg2-arg1+arg2*arg3+arg1*arg4

GK(arg1,arg2,arg3,arg4) = 2*arg1*arg4/(GB(arg1,arg2,arg3,arg4)+sqrt(GB(arg1,arg2,arg3,arg4)^2-4*(arg2-arg1)*arg1*arg4))

# parameters

# to simulate cancer: karas=1

# to simulate chloroquine treatment in cancer: karas=1, kimr’=1.5

# to simulate Vitamin C treatment in cancer: karas=1, kiras’=1.5

# to simulate PKM2 over-expression: karas=0.01, kapkm=0.5

# to simulate PKM2 depletion: karas=0.01, PKM2T=0.01

# to simulate cMyc over-expression: karas=1, cMycT=10

# to simulate cMyc depletion: karas=1, cMycT=0.1

p karas=0.01, karas’=0.1, kiras=0.1, kiras’=0, KRAST=1, Jkras=0.1

p kamr=0.01, kamr’=0.1, kamr”=2.25, kimr=0.2, kimr’=0, mTORT=1, Jmr=0.1

p kapkm=0.05, kapkm’=0.1, kapkm”=0.2, kipkm=0.2, PKM2T=1, Jpkm=0.1

p kamyc=0.01, kamyc’=0.2, kamyc”=0.2, kimyc=0.3, cMycT=1, Jmyc=0.1

p CHL=1, VitC=1

done