The natural enzyme sequestration in signaling cascades provides inherent opportunities for off-target effects induced by kinase inhibitors

MICHELLE WYNN; ALEJANDRA C VENTURA; JACQUES-A. SEPULCHRE; HECTOR J GARCIA; SOFIA D MERAJVER

Chicago

Conferencia; American Association for Cancer Research 2012 Annual Meeting; 2012

American Association for Cancer Research

Off-target effects from targeted therapies are often attributed to cross-talk, which usually refers to inter-pathway molecular interactions thatoccur because of explicit regulatory feedback connections between two pathways. Recent experimental and theoretical studies havedemonstrated, however, that covalently modified cascades naturally exhibit bidirectional signal propagation via a phenomenon termedretroactivity. This phenomenon arises due to enzyme sequestration where each cycle is coupled, not only to the next cycle, but also to theprevious cycle. While retroactivity occurs naturally in covalently modified cascades, signaling pathways likely evolved to propagateinformation in a downstream manner. An important consequence of retroactivity, however, is that a downstream perturbation can induce anupstream response without the presence of regulatory feedback connections. We hypothesize that kinase inhibitors can produce off-targeteffects as a consequence of retroactivity alone via the following mechanism: a signal travels upstream from the site of a downstreamperturbation through retroactivity and, upon reaching a shared upstream component, is delivered to an independent parallel pathway. Totest the hypothesis we used a computational model to simulate the targeted inhibition of a specific kinase in a series signaling networksusing 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-inhibitedcascade is “off” and not consuming large amounts of a shared up-stream activator. Our results also suggest that the kinetics governingcovalently modified cycles in a cascade are more important for propagating an upstream off-target effect than the binding affinity of thedrug to the targeted protein, which is a commonly optimized property in drug development. Finally, our results suggest that a singlemutation has the capacity to produce a large spontaneous off-target effect without any direct regulatory connections between the targetedprotein and the effected protein. Together, our results suggest that retroactivity may play an important role in the dysregulated signalingnetworks of cancer cells as well as the cellular response to targeted therapies. These findings have important implications for somaticevolution in cancer and the onset of therapeutic resistance, which has been widely reported for many targeted cancer therapeutics,including kinase inhibitors.