Abstract 2012: Off-target drug effects due to retroactivity in signaling pathways

Abstract

Abstract A majority of targeted cancer therapeutics involve the specific inhibition of a molecular target in a signal transduction pathway. It is well known that targeted therapies, such as kinase inhibitors, may have effects on pathways other than those specifically targeted, whether by non-specific interactions or by indirect pathway cross-talk effects. The simplest view of signal transduction entails a cascade of molecular events initiated by the recognition of a stimulus and culminating in the chemical alteration of an effector molecule. We have recently shown that cascades can exhibit bidirectional signal propagation without the addition of regulatory feedback connections via a phenomenon termed retroactivity. Thus, retroactivity represents another potential source of off-target effects in signaling cascades. We have extended our previous work to a computational model which allows us to characterize the significance of the upstream off-target effect via retroactivity with a series of simple signaling networks using physiologically relevant parameters values. We aim to understand the dynamics of cancer signaling by integrating systems biology based models of signaling dynamics into our experimental investigations of breast cancer with the intent of both directing experiments and making predictions. One of the signaling networks we studied takes the form of two independent signaling cascades which have no regulatory feedback connections but are activated by the same upstream kinase. Our results suggest that under physiologically relevant conditions the application of an inhibitor near the bottom of one cascade can produce a significant change in concentration of a protein in the other cascade, even without a regulatory feedback connection between the two cascades. Developing a deeper understanding of bidirectional signal propagation in signal transduction pathways will be vitally important in the effort to develop safer and more effective targeted cancer therapies. Our modeling results challenge the notion that information in cascades only flows in the cell surface-to-nucleus direction and suggests that a perturbation applied within a cascade can produce both an upstream and a downstream effect. The notion of an upstream off-target effect is completely novel and may have significant implications if the perturbation takes the form of an inhibitory therapeutic drug. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2012.