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.
Highlights
The ErbB receptor network consists of four members (ErbB1-4 or HER1-4): epidermal growth factor receptor (EGFR or HER1) together with human epidermal growth factor receptors HER2, HER3 and HER4
In this paper we focus on gene expression relating to receptor tyrosine kinases (RTKs) systems and downstream signalling pathways, namely PI3K/AKT and ERK1/2, which are modulated by the anti-HER2 therapies
Results revealed that trastuzumab alone inhibits pERK at a low ratio of HER3/HER2, which corresponds to HER2 overexpression (Figure 5A)
Summary
The ErbB receptor network consists of four members (ErbB1-4 or HER1-4): epidermal growth factor receptor (EGFR or HER1) together with human epidermal growth factor receptors HER2, HER3 and HER4. The ErbB receptor family belongs to the type I receptor tyrosine kinase (RTK). HER2 has no known ligands and pseudo-kinase HER3 lacks tyrosine kinase activity [1]. These features define the interactions between HER2 and HER3 receptors for forming active heterodimer and homodimer complexes. These activation kinetics depend significantly on the expression levels of. ErbB1-4 receptors and these levels vary across different cells. This combination of expression level variability and receptor interaction results in complex behaviour within the ErbB1-4 family
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