Center for Translational Medicine and Cardiology Division, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
J Am Coll Cardiol. 2013 Jan 22;61(3):267-74. doi: 10.1016/j.jacc.2012.05.066.
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.
癌症基因组学的重点在于发现增加癌症易感性或支持癌症表型的突变和染色体结构重排。蛋白激酶是癌症基因组中最常发生突变的基因，使其成为药物设计的有吸引力的治疗靶点。然而，一些激酶抑制剂 (KIs) 的使用与心脏和血管的毒性有关，包括急性冠状动脉综合征和心力衰竭。本文讨论了癌症的遗传基础，重点是导致肿瘤发生的激酶基因组 (激酶组) 中的突变。这将有助于理解现代癌症治疗的实际和潜在力量。还检查了导致 KI 心脏毒性的潜在机制。对预测心脏毒性的临床前模型（包括诱导多能干细胞和斑马鱼）进行了回顾，希望最终能够在将这些药物用于患者之前识别出有问题的药物。最后，讨论了临床中的生物标志物，并回顾了可能允许更早、更准确地检测心脏毒性的更新策略（即代谢组学和增强成像策略）。
