Abstract 2611: A multi-parameter in vitro screen demonstrates increased cardiac toxicity with pan-HER inhibitors afatinib and neratinib when used in combination with chemotherapy
Authors: Talbert Dominique R. , Doherty Kimberly , Trusk Patricia , Moran Diarmuid , Bacus Sarah 
Published: August 2015

Abstract
The human epidermal growth factor receptor 2 (HER2) oncogene is amplified and overexpressed in 25 to 30% of breast cancers and is associated with poor prognosis. Currently, two HER2-targeting agents have been FDA-approved for the treatment of these breast cancers: trastuzumab and lapatinib. Despite their proven clinical benefit, acquired resistance and reports of cardiotoxicity have limited the utility of both drugs which has led to the development of pan-HER inhibitors such as afatinib and neratinib. However, little is known about the cardiac safety profile of pan-HER inhibitors when used alone or in combination with chemotherapeutic agents as they are often utilized in the clinic. To better understand the effect of these compounds on cardiac cells, we utilized a multi-parameter in vitro toxicity screen in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). This in vitro model evaluated each drug's effect, both alone and in combination with chemotherapy, on the overall health, metabolic stress, and function of hiPSC-CM. Our results showed that although afatinib and neratinib were relatively cardiac safe at doses near their Cmax (∼150nM), higher doses of both drugs (&gt;30X Cmax) induced a range of damaging effects on cardiac health and function. Interestingly however, combination treatment with lower doses of afatinib and neratinib followed by chemotherapeutic stress led to significant cardiotoxicity including alterations in cardiac cell beating, increased lipid accumulation (indicative of mitochondrial damage), and decreased cell viability. These results suggest that although afatinib and neratinib are relatively cardiac safe when used alone at lower doses, combination regimens with these drugs and chemotherapeutic agents may increase cardiac toxicity risk. These effects are likely mediated by the inhibition of survival pathways in cardiomyocytes by pan-HER inhibitors which exacerbates chemotherapy-mediated damage. Similar effects have been shown previously for the HER2-targeted antibody trastuzumab when used in combination with anthracyclines. Together this study shows the utility of a multi-parameter in vitro screen using a more relevant hiPSC-CM model to detect potential cardiac risk for both single drug and novel combination treatments. Since many targeted therapies are given with other oncology treatments, comprehensive safety screening for combination therapies is warranted to illuminate any potential synergies on cardiotoxicity.
Citation Format: Dominique R. Talbert, Kimberly Doherty, Patricia Trusk, Diarmuid Moran, Sarah Bacus. A multi-parameter in vitro screen demonstrates increased cardiac toxicity with pan-HER inhibitors afatinib and neratinib when used in combination with chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2611. doi:10.1158/1538-7445.AM2015-2611