Abstract C280: Oncology therapeutics show unique cardiotoxic profiles in human cardiac cells.
Authors: Talbert Dominique , Doherty Kimberly , Moran Diarmuid , Wappell Robert , Trusk Patricia , Shell Scott , Bacus Sarah 
Published: August 2014

Abstract
Tyrosine Kinase Inhibitors (TKI) have greatly improved the treatment and prognosis of multiple cancer types. However unexpected clinical cardiotoxicity has been shown with some of these agents that was not wholly predicted by current preclinical toxicity assessment methods. Since cardiotoxicity with TKI are often caused by the inhibition of signaling pathways critical to cardiac cell function, multi-targeted TKI that block multiple pathways increases the likelihood for cardiac cell damage. We recently demonstrated that an in vitro multi-parameter test panel assessing the effect of drug treatment on overall cardiac health and function could accurately predict the cardiotoxicity of 4 FDA-approved TKI. The 3 multi-targeted TKI clinically associated with severe cardiac adverse events (crizotinib, sunitinib, nilotinib) all proved to be cardiotoxic in our in vitro tests while the more targeted and relatively cardiac-safe drug erlotinib showed only minor changes in cardiac cell health. The present studies expand upon this initial observation to include other TKI, chemotherapeutic agents, and non-oncology compounds which were grouped based on their known clinical toxicity profiles ranging from cardiac safe to withdrawn. We then assessed the cardiotoxic potential of these compounds by examining their effect on cell viability, reactive oxygen species (ROS) generation, lipid formation, troponin secretion and beating activity in a human induced pluripotent-derived cardiac stem (iPS) cell model. The results showed a unique cardiotoxic signature of oncology therapeutics that was significantly different from other classes of drugs such as anti-arrhythmics. Oncology compounds induced potent cell death and lipid formation (metabolic stress) in iPS cells while anti-arrhythmics more potently disrupted cardiac cell beating with minimal impact on cell viability. In addition, troponin secretion was directly correlated with cardiac cell death for all of the oncology agents. In comparison, the cardiac-safe drugs, including non-oncology compounds and more targeted TKI, did not negatively affect any of the endpoints that assessed cardiac cell health and function. Thus different classes of drugs appear to show unique toxicity profiles that may reflect multiple mechanisms which lead to cardiotoxicity. Specifically our data suggest that more promiscuous TKI which inhibit the function of multiple oncogenic targets may be affecting pathways which are critical for cardiac cell health while more targeted agents are less cardiac toxic. These studies show that a multi-parameter approach can provide a robust characterization of drug-induced cardiac cell toxicity that can be leveraged to improve drug safety during early phase development. Furthermore, these studies emphasize the importance of developing more targeted oncology agents which are effective at killing cancer cells but lack toxic effects on cardiac cells.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C280.
Citation Format: Dominique Talbert, Kimberly Doherty, Diarmuid Moran, Robert Wappell, Patricia Trusk, Scott Shell, Sarah Bacus. Oncology therapeutics show unique cardiotoxic profiles in human cardiac cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C280.