Oncology Unit, Macerata Hospital, via Santa Lucia 2, Macerata, Italy.
Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, Monte d'Ago, 60131, Ancona, Italy.
BioDrugs. 2019 Dec;33(6):613-620. doi: 10.1007/s40259-019-00382-1.
Breast cancer is the most frequent tumor in women. The recent advent of cyclin-dependent kinase (CDK) 4/6 inhibitors palbociclib and ribociclib has represented a major step forward for patients with hormone receptor-positive breast cancer. These two agents have showed similar efficacy in terms of breast cancer outcome but different cardiotoxic effects. In particular, ribociclib, but not palbociclib, has been associated with QT interval prolongation, and the mechanisms underlying this event are still unclear. In order to clarify such difference, we matched the candidate genes associated with QT interval prolongation with genes whose expression is altered following palbociclib or ribociclib treatment. We also investigated whether pharmacokinetic and pharmacodynamic characteristics, such as IC (hERG) [concentration of drug producing 50% inhibition (human ether-à-go-go related gene)] and maximum concentration (C), could justify the different effects on QT interval prolongation. Our results show that ribociclib, but not palbociclib, could act by down-regulating the expression of KCNH2 (encoding for potassium channel hERG) and up-regulating SCN5A and SNTA1 (encoding for sodium channels Nav1.5 and syntrophin-α1, respectively), three genes associated with long QT syndrome. Consistent with the cardiotoxicity induced by ribociclib, its IC (hERG)/free concentration (C) ratio is closer to the safety threshold than that of palbociclib. In summary, we hypothesize that the different cardiotoxicity associated with ribociclib and palbociclib could be due to the alteration of potassium and sodium channels induced by ribociclib. A better comprehension of the mechanisms of cardiac channelopathies and drug-induced QT interval prolongation will be fundamental to avoid serious and potentially lethal adverse events and, as a consequence, optimize the management of breast cancer patients.
乳腺癌是女性最常见的肿瘤。最近，细胞周期蛋白依赖性激酶（CDK）4/6 抑制剂哌柏西利和瑞博西利的出现代表了激素受体阳性乳腺癌患者的重大进展。这两种药物在乳腺癌结局方面具有相似的疗效，但心脏毒性作用不同。特别是，瑞博西利而不是哌柏西利与 QT 间期延长有关，其潜在机制尚不清楚。为了阐明这种差异，我们将与 QT 间期延长相关的候选基因与哌柏西利或瑞博西利治疗后表达改变的基因相匹配。我们还研究了药代动力学和药效学特征，如 hERG 抑制浓度（IC）[产生 50%抑制的药物浓度（人 Ether-a-go-go 相关基因）]和最大浓度（C）是否可以解释对 QT 间期延长的不同影响。我们的研究结果表明，瑞博西利而非哌柏西利可能通过下调 KCNH2（编码钾通道 hERG）的表达和上调 SCN5A 和 SNTA1（编码钠通道 Nav1.5 和连接蛋白-α1）的表达来发挥作用，这三个基因与长 QT 综合征有关。与瑞博西利引起的心脏毒性一致，其 IC（hERG）/游离浓度（C）比值比哌柏西利更接近安全阈值。总之，我们假设瑞博西利和哌柏西利相关的不同心脏毒性可能是由于瑞博西利引起的钾和钠通道改变所致。更好地理解心脏通道病和药物引起的 QT 间期延长的机制对于避免严重且潜在致命的不良事件至关重要，并可优化乳腺癌患者的管理。
