Defining Novel Cardiovascular Mechanisms For TKI Induced Excitability

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Project Summary/Abstract The 14 million cancer survivors living in the US clearly demonstrate continued improvements in anti- cancer treatment efficacy; yet, this success has been tempered by a parallel rise in the incidence of cancer treatment-related cardiotoxicity, leading to morbidity and mortality. A prominent example of this conundrum involves Tyrosine Kinase Inhibitors (TKIs), first-line therapy in kidney cancer, the 16th most common cause of death worldwide. Renal cell carcinoma (RCC) accounts for approximately 90% of all cases with ~143,000 deaths/year. The incidence and prevalence of RCC have been increasing over the last 50 years, and with the growth of the US elderly population, these numbers will only continue to increase. Mounting data support that TKIs can modify and inhibit cardiac voltage-gated Na+ channel Nav1.5, and in general play a key role in cardiac excitability. At the same time, TKIs have been shown to increase reactive oxygen species (ROS) in cardiomyocytes. In turn, ROS is known to activate the multifunctional Ca2+/calmodulin- dependent kinase II (CaMKII), which resides at the hub of a pro-arrhythmia signaling hub in cardiac myocytes. In previous work, we have shown that CaMKII promotes arrhythmia in part through direct phosphorylation of Nav1.5 at Ser571 with a concomitant increase in INa,L. Notably, INa,L has importance in regulating contractility in normal heart, thus of all the potential ion channels to target for cardioprotection, INa,L inhibition could prevent arrhythmias and adverse structural remodeling in patients taking TKIs. Based on these data, we will test the hypothesis that TKI-induced arrhythmia acts in part through oxidative activation of CaMKII and increased excitability cardiac myocytes. Thus, we propose INa,L is an attractive target to prevent TKI induced cardiotoxicity Results will inform clinical decision making regarding drug-induced arrhythmias, inform mechanistic approaches to prevent Ca2+ overload, and define an innovative approach using drugs readily available on the market as cardioprotective agents for patients during TKI therapy. We propose to: 1) Determine the role of TKIs in modulating cardiac myocyte excitability 2) Define the impact of TKIs on cardiac phenotypes, and 3) Define potential therapeutic strategies that mitigate TKI-induced cardiac dysfunction.