title: Systems analysis of drug-induced receptor tyrosine kinase reprogramming following targeted mono- and combination anti-cancer therapy.
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.
authors.affiliation: Scottish Informatics, Mathematics, Biology and Statistics Centre (SIMBIOS), Abertay University, Dundee, DD1 1HG, United Kingdom. a.goltsov@abertay.ac.uk.
authors.forename: Alexey
authors.initials: A
authors.lastname: Goltsov
authors.affiliation: Scottish Informatics, Mathematics, Biology and Statistics Centre (SIMBIOS), Abertay University, Dundee, DD1 1HG, United Kingdom. y.deeni@abertay.ac.uk.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Deeni
authors.affiliation: Scottish Informatics, Mathematics, Biology and Statistics Centre (SIMBIOS), Abertay University, Dundee, DD1 1HG, United Kingdom. H.Khalil@abertay.ac.uk.
authors.forename: Hilal S
authors.initials: HS
authors.lastname: Khalil
authors.affiliation: Scottish Informatics, Mathematics, Biology and Statistics Centre (SIMBIOS), Abertay University, Dundee, DD1 1HG, United Kingdom. 1305710@live.abertay.ac.uk.
authors.forename: Tero
authors.initials: T
authors.lastname: Soininen
authors.affiliation: The James Hutton Institute, Invergowrie, Dundee, DD2 5DA, United Kingdom. skyriakidis@live.com.
authors.forename: Stylianos
authors.initials: S
authors.lastname: Kyriakidis
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. huhz03@gmail.com.
authors.forename: Huizhong
authors.initials: H
authors.lastname: Hu
authors.affiliation: Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, United Kingdom. Simon.Langdon@ed.ac.uk.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Langdon
authors.affiliation: School of Medicine, University of St Andrews, St Andrews, KY16 9TF, United Kingdom. david.harrison@st-andrews.ac.uk.
authors.forename: David J
authors.initials: DJ
authors.lastname: Harrison
authors.affiliation: Scottish Informatics, Mathematics, Biology and Statistics Centre (SIMBIOS), Abertay University, Dundee, DD1 1HG, United Kingdom. J.Bown@abertay.ac.uk.
authors.forename: James
authors.initials: J
authors.lastname: Bown