Abstract 4423: Implications for cardiotoxicity with targeted therapies.
Authors: Doherty Kimberly R. , Wappel Robert L. , Talbert Dominique R. , Trusk Patricia B. , Shell Scott A. , Moran Diarmuid M. , Kramer James W. , Brown Arthur , Bacus Sarah 
Published: August 2014

Abstract
Tyrosine kinase inhibitors (TKi) have greatly improved the treatment and prognosis of multiple cancer types. However, unexpected cardiotoxicity has arisen that was not wholly predicted by current FDA mandated pre-clinical tests. Thus a more robust tool to predict the cardiotoxic potential of these compounds is warranted. For this purpose, we developed a panel of in vitro tests in a clinically relevant human cardiomyocyte model that assesses drug impact on overall cardiac health (cell viability, apoptosis, and morphology), mitochondria and metabolic intactness (reactive oxygen species (ROS) generation, AMPK activity, and lipid accumulation), and electrophysiological function (impedance (beat rate) and ion channel blockage). To demonstrate the utility of our panel, we examined the effect of 4 FDA-approved TKi with known clinical outcome on cardiac health. The 3 drugs with known cardiac adverse events (crizotinib, sunitinib, and nilotinib) all proved to be cardiotoxic by our panel although each showed distinct mechanisms of toxicity. However erlotinib, a cardiac-safe drug that targets EGFR and is used primarily in non-small cell lung cancer (NSCLC), did not show any indications of toxicity. Surprisingly, the most cardiotoxic drug by our panel was crizotinib, an ALK/ MET inhibitor that has revolutionized treatment for ALK+ NSCLC patients. Crizotinib potently impaired overall cardiac health by increasing ROS and apoptosis but also impeded electrophysiological function by inducing ion channel blockage and reducing cardiac beat rate. Interestingly crizotinib also induced lipid and cholesterol accumulation which was shown to be correlated with increased expression of the sterol-regulatory binding protein (SREBP) pathway by transcriptome analysis. The multi-targeted TKi sunitinib (used in renal cell carcinoma and gastrointestinal stromal tumors) and nilotinib (used in chronic myelogenous leukemia) also showed unique cardiotoxicity profiles. In conclusion, our studies showed a distinct cardiotoxicity profile for each TKi that correlates with clinical outcome. These results suggest that caution should be taken with these TKi especially when used long-term or in the adjuvant setting. Furthermore, these effects may be exacerbated in patients with adverse cardiac genetic predispositions and studies are ongoing in our lab on patient-derived cardiac cell lines to investigate this possibility. This multi-parameter screening approach allows for a more complete assessment of the potential for drug-induced cardiotoxicity and may allow for earlier detection in the drug development process. In addition, understanding the mechanisms of cardiac toxicities may lead to the discovery of novel mitigation strategies and combination therapies to improve cardiac cell health during treatment with oncology therapies.
Citation Format: Kimberly R. Doherty, Robert L. Wappel, Dominique R. Talbert, Patricia B. Trusk, Scott A. Shell, Diarmuid M. Moran, James W. Kramer, Arthur Brown, Sarah Bacus. Implications for cardiotoxicity with targeted therapies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4423. doi:10.1158/1538-7445.AM2013-4423