Pfizer Inc., Drug Safety Research and Development, San Diego, California.
Pfizer Inc., Drug Safety Research and Development, Groton, Connecticut.
Mol Cancer Ther. 2019 Feb;18(2):257-266. doi: 10.1158/1535-7163.MCT-18-0734. Epub 2018 Nov 6.
Recently three different cyclin-dependent kinase 4 and 6 (CDK4/6) dual inhibitors were approved for the treatment of breast cancer (palbociclib, ribociclib, and abemaciclib), all of which offer comparable therapeutic benefits. Their safety profiles, however, are different. For example, neutropenia is observed at varying incidences in patients treated with these drugs; however, it is the most common adverse event for palbociclib and ribociclib, whereas diarrhea is the most common adverse event observed in patients treated with abemaciclib. To understand the mechanism of diarrhea observed with these drugs and in an effort to guide the development of safer drugs, we compared the effects of oral administration of palbociclib, ribociclib, and abemaciclib on the gastrointestinal tract of rats using doses intended to produce comparable CDK4/6 inhibition. Rats administered abemaciclib, but not palbociclib or ribociclib, had fecal alterations, unique histopathologic findings, and distinctive changes in intestinal gene expression. Morphologic changes in the intestine were characterized by proliferation of crypt cells, loss of goblet cells, poorly differentiated and degenerating enterocytes with loss of microvilli, and mucosal inflammation. In the jejunum of abemaciclib-treated rats, downregulation of enterocyte membrane transporters and upregulation of genes associated with cell proliferation were observed, consistent with activation of the Wnt pathway and downstream transcriptional regulation. Among these CDK4/6 inhibitors, intestinal toxicity was unique to rats treated with abemaciclib, suggesting a mechanism of toxicity not due to primary pharmacology (CDK4/6 inhibition), but to activity at secondary pharmacologic targets.
最近，三种不同的细胞周期蛋白依赖性激酶 4 和 6（CDK4/6）双重抑制剂被批准用于乳腺癌的治疗（帕博西尼、瑞博西尼和阿贝西利），它们都提供了相当的治疗益处。然而，它们的安全性特征不同。例如，接受这些药物治疗的患者中性粒细胞减少的发生率不同；然而，它是帕博西尼和瑞博西尼最常见的不良反应，而腹泻是接受阿贝西利治疗的患者最常见的不良反应。为了了解这些药物引起腹泻的机制，并努力指导更安全药物的开发，我们比较了口服帕博西尼、瑞博西尼和阿贝西利在大鼠胃肠道中的作用，使用的剂量旨在产生相当的 CDK4/6 抑制。给予阿贝西利的大鼠，而不是帕博西尼或瑞博西尼，有粪便改变、独特的组织病理学发现和肠道基因表达的独特变化。肠道的形态变化表现为隐窝细胞增生、杯状细胞丧失、微绒毛丧失的未分化和退化的肠上皮细胞以及粘膜炎症。在阿贝西利治疗的大鼠空肠中，观察到肠上皮细胞膜转运蛋白的下调和与细胞增殖相关的基因的上调，这与 Wnt 途径的激活和下游转录调节一致。在这些 CDK4/6 抑制剂中，阿贝西利治疗的大鼠具有独特的肠道毒性，提示毒性机制不是由于主要药理学（CDK4/6 抑制），而是由于次要药理学靶点的活性。
