Abstract 4907: Elucidating the role of retroactive signaling and kinase inhibitors on off-target drug effects

Abstract

Abstract The primary objective of targeted cancer therapies is to modulate cancer progression by perturbing specific molecules involved in aberrant proliferation and invasion. Kinase inhibitors are targeted therapies which are designed to interfere with a specific kinase molecule in a dysregulated oncogenic signaling cascade. While extremely promising as anti-cancer agents, such inhibitors may have undesirable off-target effects, whether by non-specific interactions or by effects from pathway cross-talk. We have shown in published experimental and theoretical work that covalently modified signaling cascades naturally exhibit bidirectional signal propagation. This phenomenon is termed retroactivity and challenges the widespread notion that information in cascades only flows from the cell surface to the nucleus. Previous work has demonstrated that increasing the concentration of a phosphatase in the terminal cycle of a covalently modified cascade may result in a measurable decrease in the concentration of the previous cycle's activated kinase. Thus, a downstream perturbation in a signaling cascade can produce a reverse (or retroactive) response without the need for direct negative feedback connections. This led us to hypothesize that the use of an inhibitory drug in a signaling network may cause an upstream off-target effect simply by inhibiting the activation or deactivation of a downstream kinase. To test the hypothesis that retroactivity contributes to off-target effects, we extended our previous work to a computational model that tested a series of signaling networks. The objective of our approach was two-fold: (1) to probe the effect of retroactivity on a kinase inhibitor in a signaling network and (2) to test whether retroactivity is likely to produce a measurable off-target effect under physiologically realistic conditions. Specifically, our model simulates the targeted inhibition of an activated kinase in a series of multi-cycle networks. The results of our work indicate that at physiologically and therapeutically relevant concentrations, a targeted inhibitor may induce a measurable off-target effect via retroactivity. We also performed local sensitivity analyses to predict the kinetic parameters that most affect the off-target response. Surprisingly, the drug disassociation constant is predicted to have very little effect while parameters such as the enzyme saturation and maximum velocity of some cycles are predicted to be very important. A proper characterization of a pathway's structure is important for identifying which protein in the pathway represents the optimal drug target as well as what concentration of the targeted therapy is likely to modulate the pathway in the manner desired. We believe our results support the position that such characterizations should consider the role of retroactivity as a source of a potential off-target effects by kinase inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4907. doi:10.1158/1538-7445.AM2011-4907