Odyssey Publications

Molecular Pharmacology 2008

Multi-Pathway Model Enables Prediction Of Kinase Inhibitor Cross-Talk Effects On Migration Of HER2-Overexpressing Mammary Epithelial Cells

Neil Kumar 1, Raffi Afeyan 1, Hyung-Do Kim 1, Douglas A Lauffenburger 1*
 1-MIT

Small molecule kinase inhibitors often modulate signaling pathways other than the one targeted, whether by direct “off-target” effects or by indirect “pathway cross-talk” effects. The presence of either or both of these classes of complicating factors impedes the predictive understanding of kinase inhibitor consequences for cell phenotypic behaviors
involved in drug efficacy responses. To address this problem, we offer an avenue toward comprehending how kinase inhibitor modulations of cell signaling networks leads to altered cell phenotypic responses, by applying a quantitative, multi-pathway computational modeling approach. We show that integrating measurements of signals across three key kinase pathways involved in regulating migration of human mammary epithelial cells, downstream of ErbB system receptor activation by epidermal growth factor (EGF) or heregulin (HRG), significantly improves prediction of cell migration
changes resulting from treatment with the small molecule inhibitors LY294002 and PD98059 for both normal and HER2-overexpressing cells.

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