Systems analysis of drug-induced receptor tyrosine kinase reprogramming following targeted mono- and combination anti-cancer therapy

Alexey Goltsov*, Yusuf Y. Deeni, Hilal S. Khalil, Tero Soininen, Stylianos Kyriakidis, Huizhong Hu, Simon P. Langdon, David J. Harrison, James L. Bown

*Corresponding author for this work

Research output: Contribution to journalSpecial issue

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Abstract

The receptor tyrosine kinases (RTKs) are key drivers of cancer progression and targets for drug therapy. A major challenge in anti-RTK treatment is the dependence of drug effectiveness on co-expression of multiple RTKs which defines resistance to single drug therapy. Reprogramming of the RTK network leading to alteration in RTK co-expression in response to drug intervention is a dynamic mechanism of acquired resistance to single drug therapy in many cancers. One route to overcome this resistance is combination therapy. We describe the results of a joint in silico, in vitro, and in vivo investigations on the efficacy of trastuzumab, pertuzumab and their combination to target the HER2 receptors. Computational modelling revealed that these two drugs alone and in combination differentially suppressed RTK network activation depending on RTK co-expression. Analyses of mRNA expression in SKOV3 ovarian tumour xenograft showed up-regulation of HER3 following treatment. Considering this in a computational model revealed that HER3 up-regulation reprograms RTK kinetics from HER2 homodimerisation to HER3/HER2 heterodimerisation. The results showed synergy of the trastuzumab and pertuzumab combination treatment of the HER2 overexpressing tumour can be due to an independence of the combination effect on HER3/HER2 composition when it changes due to drug-induced RTK reprogramming.
Original languageEnglish
Pages (from-to)563-591
Number of pages29
JournalCells
Volume3
Issue number2
Early online date10 Jun 2014
DOIs
Publication statusPublished - 10 Jun 2014

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Drug Receptors
Receptor Protein-Tyrosine Kinases
Systems Analysis
Protein-Tyrosine Kinases
Systems analysis
Pharmaceutical Preparations
Drug therapy
Neoplasms
Therapeutics
Drug Therapy
Up-Regulation
Tumors
Heterografts
Computer Simulation
Substance-Related Disorders
Joints
Chemical activation
Messenger RNA
Kinetics

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Goltsov, Alexey ; Deeni, Yusuf Y. ; Khalil, Hilal S. ; Soininen, Tero ; Kyriakidis, Stylianos ; Hu, Huizhong ; Langdon, Simon P. ; Harrison, David J. ; Bown, James L. / Systems analysis of drug-induced receptor tyrosine kinase reprogramming following targeted mono- and combination anti-cancer therapy. In: Cells. 2014 ; Vol. 3, No. 2. pp. 563-591.
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abstract = "The receptor tyrosine kinases (RTKs) are key drivers of cancer progression and targets for drug therapy. A major challenge in anti-RTK treatment is the dependence of drug effectiveness on co-expression of multiple RTKs which defines resistance to single drug therapy. Reprogramming of the RTK network leading to alteration in RTK co-expression in response to drug intervention is a dynamic mechanism of acquired resistance to single drug therapy in many cancers. One route to overcome this resistance is combination therapy. We describe the results of a joint in silico, in vitro, and in vivo investigations on the efficacy of trastuzumab, pertuzumab and their combination to target the HER2 receptors. Computational modelling revealed that these two drugs alone and in combination differentially suppressed RTK network activation depending on RTK co-expression. Analyses of mRNA expression in SKOV3 ovarian tumour xenograft showed up-regulation of HER3 following treatment. Considering this in a computational model revealed that HER3 up-regulation reprograms RTK kinetics from HER2 homodimerisation to HER3/HER2 heterodimerisation. The results showed synergy of the trastuzumab and pertuzumab combination treatment of the HER2 overexpressing tumour can be due to an independence of the combination effect on HER3/HER2 composition when it changes due to drug-induced RTK reprogramming.",
author = "Alexey Goltsov and Deeni, {Yusuf Y.} and Khalil, {Hilal S.} and Tero Soininen and Stylianos Kyriakidis and Huizhong Hu and Langdon, {Simon P.} and Harrison, {David J.} and Bown, {James L.}",
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Goltsov, A, Deeni, YY, Khalil, HS, Soininen, T, Kyriakidis, S, Hu, H, Langdon, SP, Harrison, DJ & Bown, JL 2014, 'Systems analysis of drug-induced receptor tyrosine kinase reprogramming following targeted mono- and combination anti-cancer therapy', Cells, vol. 3, no. 2, pp. 563-591. https://doi.org/10.3390/cells3020563

Systems analysis of drug-induced receptor tyrosine kinase reprogramming following targeted mono- and combination anti-cancer therapy. / Goltsov, Alexey; Deeni, Yusuf Y.; Khalil, Hilal S.; Soininen, Tero; Kyriakidis, Stylianos; Hu, Huizhong; Langdon, Simon P.; Harrison, David J.; Bown, James L.

In: Cells, Vol. 3, No. 2, 10.06.2014, p. 563-591.

Research output: Contribution to journalSpecial issue

TY - JOUR

T1 - Systems analysis of drug-induced receptor tyrosine kinase reprogramming following targeted mono- and combination anti-cancer therapy

AU - Goltsov, Alexey

AU - Deeni, Yusuf Y.

AU - Khalil, Hilal S.

AU - Soininen, Tero

AU - Kyriakidis, Stylianos

AU - Hu, Huizhong

AU - Langdon, Simon P.

AU - Harrison, David J.

AU - Bown, James L.

PY - 2014/6/10

Y1 - 2014/6/10

N2 - The receptor tyrosine kinases (RTKs) are key drivers of cancer progression and targets for drug therapy. A major challenge in anti-RTK treatment is the dependence of drug effectiveness on co-expression of multiple RTKs which defines resistance to single drug therapy. Reprogramming of the RTK network leading to alteration in RTK co-expression in response to drug intervention is a dynamic mechanism of acquired resistance to single drug therapy in many cancers. One route to overcome this resistance is combination therapy. We describe the results of a joint in silico, in vitro, and in vivo investigations on the efficacy of trastuzumab, pertuzumab and their combination to target the HER2 receptors. Computational modelling revealed that these two drugs alone and in combination differentially suppressed RTK network activation depending on RTK co-expression. Analyses of mRNA expression in SKOV3 ovarian tumour xenograft showed up-regulation of HER3 following treatment. Considering this in a computational model revealed that HER3 up-regulation reprograms RTK kinetics from HER2 homodimerisation to HER3/HER2 heterodimerisation. The results showed synergy of the trastuzumab and pertuzumab combination treatment of the HER2 overexpressing tumour can be due to an independence of the combination effect on HER3/HER2 composition when it changes due to drug-induced RTK reprogramming.

AB - The receptor tyrosine kinases (RTKs) are key drivers of cancer progression and targets for drug therapy. A major challenge in anti-RTK treatment is the dependence of drug effectiveness on co-expression of multiple RTKs which defines resistance to single drug therapy. Reprogramming of the RTK network leading to alteration in RTK co-expression in response to drug intervention is a dynamic mechanism of acquired resistance to single drug therapy in many cancers. One route to overcome this resistance is combination therapy. We describe the results of a joint in silico, in vitro, and in vivo investigations on the efficacy of trastuzumab, pertuzumab and their combination to target the HER2 receptors. Computational modelling revealed that these two drugs alone and in combination differentially suppressed RTK network activation depending on RTK co-expression. Analyses of mRNA expression in SKOV3 ovarian tumour xenograft showed up-regulation of HER3 following treatment. Considering this in a computational model revealed that HER3 up-regulation reprograms RTK kinetics from HER2 homodimerisation to HER3/HER2 heterodimerisation. The results showed synergy of the trastuzumab and pertuzumab combination treatment of the HER2 overexpressing tumour can be due to an independence of the combination effect on HER3/HER2 composition when it changes due to drug-induced RTK reprogramming.

U2 - 10.3390/cells3020563

DO - 10.3390/cells3020563

M3 - Special issue

VL - 3

SP - 563

EP - 591

JO - Cells

JF - Cells

SN - 2073-4409

IS - 2

ER -