title: Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes.
abstract: Targeted therapeutics, particularly those that inhibit the activity of protein kinases that are mutated and/or overexpressed in cancer, have revolutionized the treatment of some cancers and improved survival rates in many others. Although these agents dominate drug development in cancer, significant toxicities, including cardiotoxicity, have emerged. In this Review, we examine the underlying mechanisms that result in on-target or off-target cardiotoxicities of small molecule kinase inhibitors. We also discuss how well the various preclinical safety models and strategies might predict clinical cardiotoxicity. It is hoped that a thorough understanding of the mechanisms underlying cardiotoxicity will lead to the development of safe, effective drugs and consequently, fewer costly surprises as agents progress through clinical trials.
authors.affiliation: Center for Translational Medicine, Thomas Jefferson University, 1025 Walnut Street, 316 College Building Philadelphia, Pennsylvania 19107, USA. Thomas.Force@jefferson.edu
authors.forename: Thomas
authors.initials: T
authors.lastname: Force
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Kolaja
mesh_terms: D000818:Animals; D054715:Cardiotoxins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D054715:Cardiotoxins; D047428:Protein Kinase Inhibitors