Elucidating drug mechanistics and resistance in HER2-positive breast cancer cell lines by mathematical modeling

Advancing precision medicine in the field of cancer is still curbed by the fact that a rational basis to predict treatment outcome is missing. To unravel the mechanism behind targeted drugs (trastuzumab, pertuzumab, erlotinib), mathematical modeling employing ordinary differential equations (ODE) was combined with wet-lab experimentation. Experimentation relied on systematic perturbation experiments to monitor the signaling-response towards drugs in the context of EGF signaling in the HER2+ cell lines SKBR3 and HCC1954. The impact of three different targeted drugs (trastuzumab, pertuzumab, erlotinib) on the breast cancer cell lines SKBR3 and HCC1954 was analyzed in a time-resolved manner. Each perturbation was performed as biological triplicate and the expression level of 31 different protein/phosphoproteins was monitored using reverse phase protein arrays. The selected protein/phosphoproteins are all part of the EGF signaling pathway.