********** MODEL NAME CDK4/6Inhibition-CellCycleandMitogenicPathways ********** MODEL NOTES ********** MODEL STATES d/dt(IR) = -R1 d/dt(pIR) = +R1 d/dt(PI3K) = -R2 d/dt(pPI3K) = +R2 d/dt(PIP2) = -R3 d/dt(PIP3) = +R3 d/dt(PDK1) = -R4 d/dt(aPDK1) = +R4 d/dt(mTORC2) = -R5 d/dt(amTORC2) = +R5 d/dt(AKT) = -R6 d/dt(pAKT308) = +R6-R7 d/dt(ppAKT308473) = +R7 d/dt(mTORC1) = -R8 d/dt(amTORC1) = +R8 d/dt(S6K) = -R9 d/dt(pS6K) = +R9 d/dt(FGFR) = -R10 d/dt(pFGFR) = +R10 d/dt(Ras) = -R11 d/dt(aRas) = +R11 d/dt(Raf) = -R12 d/dt(aRaf) = +R12 d/dt(MEK) = -R13 d/dt(pMEK) = +R13 d/dt(ERK) = -R14 d/dt(pERK) = +R14 d/dt(ERa) = -R15 d/dt(aERa) = +R15 d/dt(Myc) = +R16-R17-R18 d/dt(pMyc) = +R18 d/dt(GSK3b) = -R19 d/dt(pGSK3b) = +R19 d/dt(FOXO3) = -R20 d/dt(pFOXO3) = +R20 d/dt(cycD) = +R21-R22-R27 d/dt(cycE) = +R23-R24-R28 d/dt(cycA) = +R25-R26-R29 d/dt(CDK46) = -R27 d/dt(CDK2) = -R28-R29 d/dt(CDK46cycD) = +R27 d/dt(CDK2cycE) = +R28 d/dt(CDK2cycA) = +R29 d/dt(p2127) = -R30 d/dt(pp2127) = +R30 d/dt(E2F) = +R31-R32-R33 d/dt(RbE2F) = +R33 d/dt(Rb) = -R33-R34 d/dt(pRb) = +R34-R35 d/dt(pppRb) = +R35 IR(0) = 100 pIR(0) = 0 PI3K(0) = 100 pPI3K(0) = 0 PIP2(0) = 100 PIP3(0) = 0 PDK1(0) = 100 aPDK1(0) = 0 mTORC2(0) = 100 amTORC2(0) = 0 AKT(0) = 100 pAKT308(0) = 0 ppAKT308473(0) = 0 mTORC1(0) = 100 amTORC1(0) = 0 S6K(0) = 100 pS6K(0) = 0 FGFR(0) = 100 pFGFR(0) = 0 Ras(0) = 100 aRas(0) = 0 Raf(0) = 100 aRaf(0) = 0 MEK(0) = 100 pMEK(0) = 0 ERK(0) = 100 pERK(0) = 0 ERa(0) = 100 aERa(0) = 0 Myc(0) = 0 pMyc(0) = 0 GSK3b(0) = 100 pGSK3b(0) = 0 FOXO3(0) = 100 pFOXO3(0) = 0 cycD(0) = 0 cycE(0) = 0 cycA(0) = 0 CDK46(0) = 100 CDK2(0) = 100 CDK46cycD(0) = 0 CDK2cycE(0) = 0 CDK2cycA(0) = 0 p2127(0) = 100 pp2127(0) = 0 E2F(0) = 0 RbE2F(0) = 0 Rb(0) = 100 pRb(0) = 0 pppRb(0) = 0 ********** MODEL PARAMETERS kc1f1 = 0.1 Vmax1r1 = 10 kc2f1 = 0.1 Ki2 = 0.1 kc2f2 = 0.1 Vmax2r1 = 10 kc3f1 = 0.1 Vmax3r1 = 10 kc3r1 = 0.1 kc4f1 = 0.1 Vmax4r1 = 10 kc5f1 = 0.1 Ki5 = 0.01 Vmax5r1 = 10 kc6f1 = 0.1 Vmax6r1 = 10 kc7f1 = 0.1 alpha7 = 0.01 Vmax7r1 = 10 kc8f1 = 0.1 Vmax8r1 = 10 kc9f1 = 0.1 Vmax9r1 = 10 kc10f1 = 0.1 alpha10 = 0.01 Vmax10r1 = 10 kc11f1 = 0.1 kc11f2 = 0.1 Ki11 = 0.01 Vmax11r1 = 10 kc12f1 = 0.1 Ki12 = 0.01 Vmax12r1 = 10 kc13f1 = 0.1 Vmax13r1 = 10 kc14f1 = 0.1 Vmax14r1 = 10 kc15f1 = 0.1 alpha15 = 0.01 Ki15 = 0.01 Vmax15r1 = 10 kc16f1 = 0.001 alpha16a = 0.01 alpha16b = 0.01 kc16f2 = 0.001 kdeg17f1 = 0.1 alpha17 = 0.1 kc18f1 = 0.1 Vmax18r1 = 10 kc19f1 = 0.1 Vmax19r1 = 10 kc20f1 = 0.1 Vmax20r1 = 10 kc21f1 = 0.1 kc21f2 = 0.1 kc21f3 = 0.1 kc21f4 = 0.1 alpha21a = 0.01 alpha21b = 0.01 kdeg22f1 = 1 alpha22 = 0.1 kc23f1 = 0.1 alpha23 = 0.01 kc23f2 = 0.1 kdeg24f1 = 0.1 alpha24 = 0.1 kc25f1 = 0.1 alpha25 = 0.01 kc25f2 = 0.1 kdeg26f1 = 0.1 ka27f1 = 0.001 alpha27 = 0.01 Ki27 = 0.01 kd27r1 = 0.01 ka28f1 = 0.001 Ki28 = 0.01 kd28r1 = 0.01 ka29f1 = 0.001 alpha29 = 0.01 kd29r1 = 0.01 kc30f1 = 0.1 alpha30 = 0.01 Vmax30r1 = 10 kc31f1 = 0.1 kc31f2 = 0.1 kdeg32f1 = 0.1 ka33f1 = 0.001 kd33r1 = 0.01 kc34f1 = 0.1 Vmax34r1 = 10 kc35f1 = 0.1 Vmax35r1 = 10 PTEN = 100 AKTscale = 5 Ins_0 = 100 FGF_0 = 100 Est_0 = 100 Ei = 10 CDK46i = 10 Ins_on = 5000 FGF_on = 5000 Est_on = 5000 Ei_on = 10000 CDK46i_on = 10000 ********** MODEL VARIABLES IR_Total = IR+pIR PI3K_Total = PI3K+pPI3K PIP_Total = PIP2+PIP3 PDK1_Total = PDK1+aPDK1 mTORC2_Total = mTORC2+amTORC2 AKT_Total = AKT+pAKT308+ppAKT308473 mTORC1_Total = mTORC1+amTORC1 S6K_Total = S6K+pS6K FGFR_Total = FGFR+pFGFR Ras_Total = Ras+aRas Raf_Total = Raf+aRaf MEK_Total = MEK+pMEK ERK_Total = ERK+pERK ERa_Total = ERa+aERa GSK3b_Total = GSK3b+pGSK3b FOXO3_Total = FOXO3+pFOXO3 CDK46_Total = CDK46+CDK46cycD CDK2_Total = CDK2+CDK2cycE+CDK2cycA p2127_Total = p2127+pp2127 Rb_Total = Rb+pRb+pppRb Ins = Ins_0*piecewiseIQM(1,ge(time,Ins_on),0) FGF = FGF_0*piecewiseIQM(1,ge(time,FGF_on),0) Est = Est_0*piecewiseIQM(1,ge(time,Est_on),0) Ei_0 = Ei*piecewiseIQM(1,ge(time,Ei_on),0) CDK46i_0 = CDK46i*piecewiseIQM(1,ge(time,CDK46i_on),0) ********** MODEL REACTIONS R1 = (kc1f1*Ins*IR)- ((Vmax1r1*pIR)) {reversible} R2 = (((kc2f1*pIR*PI3K)/(1+(pS6K/Ki2)))+(kc2f2*pFGFR*PI3K))- ((Vmax2r1*pPI3K)) {reversible} R3 = (kc3f1*pPI3K*PIP2)- (((Vmax3r1+kc3r1*PTEN)*PIP3)) {reversible} R4 = (kc4f1*PIP3*PDK1)- ((Vmax4r1*aPDK1)) {reversible} R5 = ((kc5f1*PIP3*mTORC2)/(1+(pppRb/Ki5)))- ((Vmax5r1*amTORC2)) {reversible} R6 = (kc6f1*aPDK1*AKT)- ((Vmax6r1*pAKT308)) {reversible} R7 = ((kc7f1*amTORC2*pAKT308)*(1+(alpha7*CDK2cycA)))- ((Vmax7r1*ppAKT308473)) {reversible} R8 = ((kc8f1*pAKT308+AKTscale*kc8f1*ppAKT308473)*mTORC1)- ((Vmax8r1*amTORC1)) {reversible} R9 = (kc9f1*amTORC1*S6K)- ((Vmax9r1*pS6K)) {reversible} R10 = ((kc10f1*FGF*FGFR)*(1+(alpha10*E2F)))- ((Vmax10r1*pFGFR)) {reversible} R11 = (((kc11f1*pFGFR+kc11f2*pIR)*Ras)/(1+(pERK/Ki11)))- ((Vmax11r1*aRas)) {reversible} R12 = ((kc12f1*aRas*Raf)/(1+(pAKT308/Ki12)+(ppAKT308473/(AKTscale*Ki12))))- ((Vmax12r1*aRaf)) {reversible} R13 = (kc13f1*aRaf*MEK)- ((Vmax13r1*pMEK)) {reversible} R14 = (kc14f1*pMEK*ERK)- ((Vmax14r1*pERK)) {reversible} R15 = (((kc15f1*Est*ERa)*(1+(alpha15*FOXO3)))/(1+(Ei_0/Ki15)))- ((Vmax15r1*aERa)) {reversible} R16 = (((kc16f1*aERa)*(1+(alpha16a*pERK)+(alpha16b*cycD)))+(kc16f2*E2F)) R17 = ((kdeg17f1*Myc)*(1+(alpha17*GSK3b))) R18 = (kc18f1*pERK*Myc)- ((Vmax18r1*pMyc)) {reversible} R19 = ((kc19f1*pAKT308+AKTscale*kc19f1*ppAKT308473)*GSK3b)- ((Vmax19r1*pGSK3b)) {reversible} R20 = ((kc20f1*pAKT308+AKTscale*kc20f1*ppAKT308473)*FOXO3)- ((Vmax20r1*pFOXO3)) {reversible} R21 = ((kc21f1*amTORC1)+(kc21f2*pERK)+(kc21f3*(Myc+pMyc))+((kc21f4*aERa)*(1+(alpha21a*pERK)+(alpha21b*cycD)))) R22 = ((kdeg22f1*cycD)*(1+(alpha22*GSK3b))) R23 = (((kc23f1*E2F)*(1+(alpha23*(Myc+pMyc))))+(kc23f2*(Myc+pMyc))) R24 = (kdeg24f1*cycE)*(1+(alpha24*GSK3b)) R25 = (((kc25f1*E2F)*(1+(alpha25*(Myc+pMyc))))+((kc25f2*(Myc+pMyc)))) R26 = (kdeg26f1*cycA) R27 = (((ka27f1*CDK46*cycD)*(1+(alpha27*pp2127)))/(1+(CDK46i_0/Ki27)))- ((kd27r1*CDK46cycD)) {reversible} R28 = ((ka28f1*CDK2*cycE)/(1+(p2127/Ki28)))- ((kd28r1*CDK2cycE)) {reversible} R29 = ((ka29f1*CDK2*cycA)*(1+(alpha29*pAKT308)+(AKTscale*alpha29*ppAKT308473)))- ((kd29r1*CDK2cycA)) {reversible} R30 = ((((kc30f1*pAKT308)+(AKTscale*kc30f1*ppAKT308473))*p2127)*(1+(alpha30*(Myc+pMyc))))- ((Vmax30r1*pp2127)) {reversible} R31 = ((kc31f1*(Myc+pMyc))+(kc31f2*E2F)) R32 = (kdeg32f1*E2F) R33 = (ka33f1*E2F*Rb)- ((kd33r1*RbE2F)) {reversible} R34 = (kc34f1*CDK46cycD*Rb)- ((Vmax34r1*pRb)) {reversible} R35 = (kc35f1*CDK2cycE*pRb)- ((Vmax35r1*pppRb)) {reversible} ********** MODEL FUNCTIONS ********** MODEL EVENTS ********** MODEL MATLAB FUNCTIONS