Cells 2014, 3(2), 563-591; doi:10.3390/cells3020563
Review

Systems Analysis of Drug-Induced Receptor Tyrosine Kinase Reprogramming Following Targeted Mono- and Combination Anti-Cancer Therapy

Received: 31 March 2014; in revised form: 14 May 2014 / Accepted: 19 May 2014 / Published: 10 June 2014
(This article belongs to the Special Issue Receptor Tyrosine Kinases)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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.
Keywords: HER2; HER3; trastuzumab; pertuzumab; combination cancer therapy; signalling reprogramming
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MDPI and ACS Style

Goltsov, A.; Deeni, Y.; Khalil, H.S.; Soininen, T.; Kyriakidis, S.; Hu, H.; Langdon, S.P.; Harrison, D.J.; Bown, J. Systems Analysis of Drug-Induced Receptor Tyrosine Kinase Reprogramming Following Targeted Mono- and Combination Anti-Cancer Therapy. Cells 2014, 3, 563-591.

AMA Style

Goltsov A, Deeni Y, Khalil HS, Soininen T, Kyriakidis S, Hu H, Langdon SP, Harrison DJ, Bown J. Systems Analysis of Drug-Induced Receptor Tyrosine Kinase Reprogramming Following Targeted Mono- and Combination Anti-Cancer Therapy. Cells. 2014; 3(2):563-591.

Chicago/Turabian Style

Goltsov, Alexey; Deeni, Yusuf; Khalil, Hilal S.; Soininen, Tero; Kyriakidis, Stylianos; Hu, Huizhong; Langdon, Simon P.; Harrison, David J.; Bown, James. 2014. "Systems Analysis of Drug-Induced Receptor Tyrosine Kinase Reprogramming Following Targeted Mono- and Combination Anti-Cancer Therapy." Cells 3, no. 2: 563-591.

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