Boolean ErbB network reconstructions and perturbation simulations reveal individual drug response in different breast cancer cell lines

Silvia Von der Heyde, Christian Bender, Frauke Henjes, Johanna Sonntag, Ulrike Korf, Tim Beißbarth

Despite promising progress in targeted breast cancer therapy, drug resistance remains challenging.The monoclonal antibody drugs trastuzumab and pertuzumab as well as the small molecule inhibitorerlotinib were designed to prevent ErbB-2 and ErbB-1 receptor induced deregulated proteinsignalling, contributing to tumour progression. The oncogenic potential of ErbB receptors unfolds incase of overexpression or mutations. Dimerisation with other receptors allows to bypass pathwayblockades. Our intention is to reconstruct the ErbB network to reveal resistance mechanisms. Weused longitudinal proteomic data of ErbB receptors and downstream targets in the ErbB-2 amplifiedbreast cancer cell lines BT474, SKBR3 and HCC1954 treated with erlotinib, trastuzumab orpertuzumab, alone or combined, up to 60 minutes and 30 hours, respectively. In a Boolean modellingapproach, signalling networks were reconstructed based on these data in a cell line and time coursespecific manner, including prior literature knowledge. Finally, we simulated network response toinhibitor combinations to detect signalling nodes reflecting growth inhibition.