ORIGINAL PAPER Systems pharmacological analysis of mitochondrial cardiotoxicity induced by selected tyrosine kinase inhibitors Tanaya Vaidya 1 • Jeff Kamta 1 • Maher Chaar 1 • Anusha Ande 1 • Sihem Ait-Oudhia 1 Received: 13 October 2017 / Accepted: 5 February 2018 Ó Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Tyrosine kinase inhibitors (TKIs) are targeted therapies rapidly becoming favored over conventional cytotoxic chemotherapeutics. Our study investigates two FDA approved TKIs, DASATINIB; indicated for IMATINIB-refractory chronic myeloid leukemia, and SORAFENIB; indicated for hepatocellular carcinoma and advanced renal cell carcinoma. Limited but crucial evidence suggests that these agents can have cardiotoxic side effects ranging from hypertension to heart failure. A greater understanding of the underlying mechanisms of this cardiotoxicity are needed as concerns grow and the capacity to anticipate them is lacking. The objective of this study was to explore the mitochondrial-mediated cardiotoxic mechanisms of the two selected TKIs. This was achieved experimentally using immortalized human cardiomyocytes, AC16 cells, to investigate dose- and time-dependent cell killing, along with measurements of temporal changes in key signaling proteins involved in the intrinsic apoptotic and autophagy pathways upon exposure to these agents. Quantitative systems phar- macology (QSP) models were developed to capture the toxicological response in AC16 cells using protein dynamic data. The developed QSP models captured well all the various trends in protein signaling and cellular responses with good precision on the parameter estimates, and were successfully qualified using external data sets. An interplay between the apoptotic and autophagic pathways was identified to play a major role in determining toxicity associated with the investigated TKIs. The established modeling platform showed utility in elucidating the mechanisms of cardiotoxicity of SORAFENIB and DASATINIB. It may be useful for other small molecule targeted therapies demonstrating cardiac toxicities, and may aid in informing alternate dosing strategies to alleviate cardiotoxicity associated with these therapies. Keywords Cardiotoxicity Á Tyrosine kinase inhibitors (TKIs) Á DASATINIB Á SORAFENIB Á Quantitative systems pharmacology (QSP) models Abbreviations Akt AKT8 virus oncogene cellular homolog ASK1 Apoptosis signal-regulating kinase 1 AT2 Angiotensin II receptor type 2 ATP Adenosine triphosphate BAD Bcl-2-associated death promoter Bcl-2 B-cell lymphoma 2 protein Bcl-xL B-cell lymphoma-extra large protein Bcr-Abl Fusion protein encoded by the Philadelphia chromosome c-Kit Stem cell growth factor receptor DMSO Dimethyl sulfoxide FBS Fetal bovine serum GAPDH Glyceraldehyde 3-phosphate dehydrogenase JNK Jun N-terminal kinase LC3 Microtubule-associated protein 1 light chain 3 MST2 Serine/threonine kinase 3 (STK3) mTORC1 Mammalian target of rapamycin complex 1 PDGFR Platelet derived growth factor receptor phospho-Akt/ pAkt Phosphorylated Akt phospho-BAD/ pBAD Phosphorylated BAD Phospho-Bcl2/ pBcl2 Phosphorylated Bcl-2 & Sihem Ait-Oudhia sihem.bihorel@cop.ufl.edu 1 Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, 6550 Sanger Road, Office: 469, Orlando, FL 32827, USA 123 Journal of Pharmacokinetics and Pharmacodynamics https://doi.org/10.1007/s10928-018-9578-9