title: A multi-parameter in vitro screen in human stem cell-derived cardiomyocytes identifies ponatinib-induced structural and functional cardiac toxicity.
abstract: Ponatinib, a multi-targeted TKI and potent pan-ABL inhibitor, approved for the treatment of Ph + ALL and CML, was temporarily withdrawn from the U.S. market due to severe vascular adverse events. Cardiac-specific toxicities including myocardial infarction, severe congestive heart failure, and cardiac arrhythmias have also been shown with ponatinib. Targeted oncology agents such as ponatinib have transformed cancer treatment but often induce toxicity due to inhibition of survival pathways shared by both cancer and cardiac cells. These toxicities are often missed by the standard preclinical toxicity assessment methods, which include human Ether-à-go-go-related gene (hERG) and animal toxicity testing. In this study, we show that a multiparameter in vitro toxicity screening approach using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) accurately predicted the cardiac toxicity potential of ponatinib. This in vitro model evaluated ponatinib's effect on the overall cell health, mitochondrial stress, and function of hiPSC-CM and also provided mechanistic insight into the signaling pathways and cellular structures altered with treatment. We show here that ponatinib rapidly inhibits prosurvival signaling pathways, induces structural cardiac toxicity (as shown by actin cytoskeleton damage, mitochondrial stress, cell death, and troponin secretion), and disrupts cardiac cell beating. Most of these effects occurred at doses between 10× and 50× ponatinib's Cmax, a dose range shown to be relevant for accurate prediction of in vivo toxicity. Together these studies show that a comprehensive in vitro screening tool in a more relevant human cardiac cell model can improve the detection of cardiac toxicity with targeted oncology agents such as ponatinib.
authors.affiliation: Quintiles Inc., Translational R&D-Oncology, 777 Oakmont Lane Suite No. 100, Westmont, Illinois 60559 Dominique.talbert@quintiles.com.
authors.forename: Dominique R
authors.initials: DR
authors.lastname: Talbert
authors.affiliation: Quintiles Inc., Translational R&D-Oncology, 777 Oakmont Lane Suite No. 100, Westmont, Illinois 60559.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Doherty
authors.affiliation: Quintiles Inc., Translational R&D-Oncology, 777 Oakmont Lane Suite No. 100, Westmont, Illinois 60559.
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Trusk
authors.affiliation: Quintiles Inc., Translational R&D-Oncology, 777 Oakmont Lane Suite No. 100, Westmont, Illinois 60559.
authors.forename: Diarmuid M
authors.initials: DM
authors.lastname: Moran
authors.affiliation: Quintiles Inc., Translational R&D-Oncology, 777 Oakmont Lane Suite No. 100, Westmont, Illinois 60559.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Shell
authors.affiliation: Quintiles Inc., Translational R&D-Oncology, 777 Oakmont Lane Suite No. 100, Westmont, Illinois 60559.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bacus
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000633:toxicity*; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011724:Pyridazines / Q000633:toxicity*; D018570:Risk Assessment; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods*; D014336:Troponin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D014336:Troponin; C545373:ponatinib
keywords: ABL inhibitors; cardiac toxicity; human stem cell-derived cardiomyocytes; in vitro toxicity testing; targeted oncology agents