title: Cancer genetics and the cardiotoxicity of the therapeutics.
abstract: Cancer genomics has focused on the discovery of mutations and chromosomal structural rearrangements that either increase susceptibility to cancer or support the cancer phenotype. Protein kinases are the most frequently mutated genes in the cancer genome, making them attractive therapeutic targets for drug design. However, the use of some of the kinase inhibitors (KIs) has been associated with toxicities to the heart and vasculature, including acute coronary syndromes and heart failure. Herein we discuss the genetic basis of cancer, focusing on mutations in the kinase genome (kinome) that lead to tumorigenesis. This will allow an understanding of the real and potential power of modern cancer therapeutics. The underlying mechanisms that drive the cardiotoxicity of the KIs are also examined. The preclinical models for predicting cardiotoxicity, including induced pluripotent stem cells and zebrafish, are reviewed, with the hope of eventually being able to identify problematic agents before their use in patients. Finally, the use of biomarkers in the clinic is discussed, and newer strategies (i.e., metabolomics and enhanced imaging strategies) that may allow earlier and more accurate detection of cardiotoxicity are reviewed.
authors: Center for Translational Medicine and Cardiology Division, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
authors: Hind
authors: H
authors: Lal
authors: Kyle L
authors: KL
authors: Kolaja
authors: Thomas
authors: T
authors: Force
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D054715:Cardiotoxins / Q000009:adverse effects / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D004260:DNA Repair; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015894:Genome, Human; D006321:Heart / Q000187:drug effects*; D006801:Humans; D055432:Metabolomics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D017410:Practice Guidelines as Topic; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D011494:Protein Kinases / Q000187:drug effects; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D054715:Cardiotoxins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases