Cardiovascular Effects of the MEK Inhibitor, Trametinib: A Case Report, Literature Review, and Consideration of Mechanism.
Cardiovascular Effects of the MEK Inhibitor, Trametinib: A Case Report, Literature Review, and Consideration of Mechanism.
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DOI：
10.1007/s12012-017-9425-z
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发表时间：
2017-10
影响因子：
3.2
通讯作者：
Jensen BC
中科院分区：
文献类型：
--
作者：
Banks M;Crowell K;Proctor A;Jensen BC
MEK抑制剂曲美替尼于2013年被批准用于治疗具有BRAF V600 E突变的不可切除或转移性黑色素瘤，BRAF V600 E突变是黑色素瘤中最常见的致病突变。曲美替尼阻断ERK 1/2的激活，抑制黑色素瘤细胞增殖。ERK 1/2还在小鼠模型中保护免受多种类型的心脏损伤。曲美替尼改善黑色素瘤患者的生存率，但意外的心脏毒性的证据正在出现。在这里，我们描述的情况下，转移性黑色素瘤患者发生急性收缩性心力衰竭曲美替尼治疗后，并提出了由这种情况下提示的文献综述的结果。1例无心脏病史的患者出现6.5 mm皮肤病变，发现转移性BRAF V600 E黑色素瘤。开始曲美替尼和BRAF抑制剂达拉非尼的联合治疗。患者治疗前射血分数为55- 60%。他的EF在13天后下降，在治疗后1个月为40%。开始曲美替尼治疗后两个月，患者出现呼吸困难和疲乏。我们在电子病历中进行了病历审查。我们使用曲美替尼/不良反应和（“心力衰竭”或“左心室功能障碍”或高血压或心脏毒性或死亡率）进行了PubMed检索。我们还查询了FDA不良事件报告系统，以了解2013年1月1日至2017年7月20日期间与曲美替尼相关的心肌病、射血分数降低和左心室功能障碍报告。文献检索检索到19篇文章，包括临床试验和病例报告。MEK抑制剂曲美替尼的早期临床经验表明，其临床疗效可能会受到心脏毒性的影响。需要对人类和动物进行进一步研究，以确定这种不良影响的程度及其潜在机制。
The MEK inhibitor trametinib was approved in 2013 for the treatment of unresectable or metastatic melanoma with a BRAF V600E mutation, the most common pathogenic mutation in melanoma. Trametinib blocks activation of ERK1/2, inhibiting cell proliferation in melanoma. ERK1/2 also protects against multiple types of cardiac insult in mouse models. Trametinib improves survival in melanoma patients, but evidence of unanticipated cardiotoxicity is emerging. Here we describe the case of a patient with metastatic melanoma who developed acute systolic heart failure after trametinib treatment and present the results of the literature review prompted by this case. A patient with no cardiac history presented with a 6.5-mm skin lesion and was found to have metastatic BRAF V600E melanoma. Combination treatment with trametinib and the BRAF inhibitor, dabrafenib, was initiated. The patient’s pre-treatment ejection fraction was 55–60%. His EF declined after 13 days and that was 40% 1 month after treatment. Two months after initiating trametinib, he developed dyspnea and fatigue. We conducted a chart review in the electronic medical record. We conducted a PubMed search using trametinib/adverse effects AND (“heart failure” OR “left ventricular dysfunction” OR hypertension OR cardiotoxicity OR mortality). We also queried the FDA Adverse Events Reporting System for reports of cardiomyopathy, ejection fraction decrease, and left ventricular dysfunction associated with trametinib between January 1, 2013, and July 20, 2017. The literature search retrieved 19 articles, including clinical trials and case reports. Early clinical experience with the MEK inhibitor trametinib suggests that its clinical efficacy may be compromised by cardiotoxicity. Further studies in humans and animals are required to determine the extent of this adverse effect, as well as its underlying mechanisms.
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通讯作者：
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