Abstract 4925: The natural enzyme sequestration in signaling cascades provides inherent opportunities for off-target effects induced by kinase inhibitors
Michelle L. Wynn, Alejandra C. Ventura, Jacques-A. Sepulchre, Héctor J. García, Sofia Diana Merajver · Cancer Research · 2012
Abstract Off-target effects from targeted therapies are often attributed to cross-talk, which usually refers to inter-pathway molecular interactions that occur because of explicit regulatory feedback connections between two pathways. Recent experimental and theoretical studies have demonstrated, however, that covalently modified cascades naturally exhibit bidirectional signal propagation via a phenomenon termed retroactivity. This phenomenon arises due to enzyme sequestration where each cycle is coupled, not only to the next cycle, but also to the previous cycle. While retroactivity occurs naturally in covalently modified cascades, signaling pathways likely evolved to propagate information in a downstream manner. An important consequence of retroactivity, however, is that a downstream perturbation can induce an upstream response without the presence of regulatory feedback connections. We hypothesize that kinase inhibitors can produce off-target effects as a consequence of retroactivity alone via the following mechanism: a signal travels upstream from the site of a downstream perturbation through retroactivity and, upon reaching a shared upstream component, is delivered to an independent parallel pathway. To test the hypothesis we used a computational model to simulate the targeted inhibition of a specific kinase in a series signaling networks using physiologically and therapeutically relevant ranges for all parameters. Surprisingly, our results suggest that an off-target effect due to retroactive signaling is more likely when the first cycle in a non-inhibited cascade is “off” and not consuming large amounts of a shared up-stream activator. Our results also suggest that the kinetics governing covalently modified cycles in a cascade are more important for propagating an upstream off-target effect than the binding affinity of the drug to the targeted protein, which is a commonly optimized property in drug development. Finally, our results suggest that a single mutation has the capacity to produce a large spontaneous off-target effect without any direct regulatory connections between the targeted protein and the effected protein. Together, our results suggest that retroactivity may play an important role in the dysregulated signaling networks of cancer cells as well as the cellular response to targeted therapies. These findings have important implications for somatic evolution in cancer and the onset of therapeutic resistance, which has been widely reported for many targeted cancer therapeutics, including kinase inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4925. doi:1538-7445.AM2012-4925