Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2- advanced breast cancer.
Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2- advanced breast cancer.
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DOI：
10.2147/dddt.s137783
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Generali D
中科院分区：
文献类型：
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作者：
Corona SP;Generali D
尽管早期乳腺癌（BC）的治愈率很高，但晚期或转移性疾病在医疗管理和治疗决策方面提出了许多挑战，并且与明显较差的预后相关。在新的靶向药物中，利用细胞周期机制的抗癌药物在临床前研究中显示出巨大的潜力。 CDK4/6 抑制剂靶向细胞周期蛋白 D/CDK/视网膜母细胞瘤信号通路，诱导细胞周期停滞、细胞活力降低和肿瘤缩小。由于细胞周期蛋白 D/CDK 复合物在雌激素信号传导下游被激活，CDK4/6 抑制剂与标准内分泌疗法的组合代表了在激素受体阳性 BC 中引发协同抗肿瘤活性的合理方法。临床试验结果确实证实了CDK4/6抑制剂联合内分泌治疗相对于单独内分泌治疗的优越性。目前批准的三种化合物具有相似的结构特征以及生物和临床活性。 Abemaciclib是美国食品药品监督管理局（FDA）根据MONARCH 1和2试验的结果批准的最新CDK4/6抑制剂。进一步的试验正在进行中，其他重要问题等待答复。在这篇综述中，我们重点关注 abemaciclib 来检查临床前和临床结果，描述当前的治疗适应症、悬而未决的问题和正在进行的临床试验。
Although early breast cancer (BC) is highly curable, advanced or metastatic disease poses numerous challenges in terms of medical management and treatment decisions and is associated with significantly worse prognosis. Among the new targeted agents, anticancer drugs exploiting the cell-cycle machinery have shown great potential in preclinical studies. CDK4/6 inhibitors target the cyclin D/CDK/retinoblastoma signaling pathway, inducing cell-cycle arrest, reduced cell viability and tumor shrinking. As the cyclin D/CDK complex is activated downstream of estrogen signaling, the combination of CDK4/6 inhibitors with standard endocrine therapies represents a rational approach to elicit synergic antitumor activity in hormone receptor-positive BC. The results of clinical trials have indeed confirmed the superiority of the combination of CDK4/6 inhibitors plus endocrine therapies over endocrine therapy alone. Currently approved are three compounds that exhibit similar structural characteristics as well as biological and clinical activities. Abemaciclib is the latest CDK4/6 inhibitor approved by the US Food and Drug Administration (FDA) in view of the results of the MONARCH 1 and 2 trials. Further trials are ongoing as other important questions await response. In this review, we focus on abemaciclib to examine preclinical and clinical results, describing current therapeutic indications, open questions and ongoing clinical trials.