Abstract 3674: Targeted oncology therapeutics show unique cardiotoxic profiles: Ponatinib as a case study
Authors: Talbert Dominique , Doherty Kimberly , Trusk Patricia , Moran Diarmuid , Shell Scott , Bacus Sarah 
Published: May 2015

Although tyrosine kinase inhibitors (TKI) have greatly improved the treatment and prognosis of multiple cancer types, unexpected clinical cardiotoxicity has occurred with some of these agents that was not predicted by standard preclinical toxicity assessment methods. Since cardiotoxicity with TKI are often caused by the inhibition of signaling pathways that are critical to cardiac cell function, multi-targeted TKI that block multiple pathways increase 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 four FDA-approved TKI. The multi-targeted TKI that are clinically associated with cardiac adverse events (crizotinib, sunitinib, nilotinib) all proved to be cardiotoxic in our in vitro tests while a more targeted and relatively cardiac-safe drug, erlotinib, showed only minor changes in cardiac cell health. The present studies expand upon this initial observation using a broad panel of drugs such as TKI (including the recently withdrawn TKI ponatinib), chemotherapeutic agents, and non-oncology compounds, which were grouped based on their known clinical toxicity profiles ranging from cardiac safe to withdrawn. We assessed each compound's cardiotoxic potential 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 drug classes. Oncology compounds, including ponatinib, induced metabolic stress (ROS generation and lipid formation) resulting in potent cardiac cell death and troponin secretion while other classes of drugs disrupted cardiac cell beating with minimal impact on cardiac cell health. In comparison, cardiac-safe drugs, including non-oncology compounds and more targeted TKI, did not impact any of the endpoints that assessed cardiac cell health and function. Our results demonstrate unique toxicity profiles for different drug classes which may reflect multiple mechanisms of cardiotoxicity. For oncology compounds specifically, multi-targeted TKI and chemotherapeutic agents show potent cardiac toxicity while more targeted agents are less cardiac toxic. These studies show that a multi-parameter approach provides a comprehensive and robust assessment of cardiotoxic potential by evaluating several parameters that are important to cardiac cell health and function in a more predictive adult cardiac cell model. A panel such as this aids in early risk assessment of cardiotoxic compounds and may reduce drug failure due to toxicity discovered in later phases of development or after drug approval such as that shown with ponatinib.

Citation Format: Dominique Talbert, Kimberly Doherty, Patricia Trusk, Diarmuid Moran, Scott Shell, Sarah Bacus. Targeted oncology therapeutics show unique cardiotoxic profiles: Ponatinib as a case study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3674. doi:10.1158/1538-7445.AM2014-3674