Discovery Chemistry Research and Technology, Eli Lilly and Company, Madrid, Spain.
Eli Lilly and Company, Indianapolis, IN 46225, USA.
Oncotarget. 2022 Jul 2;13:864-875. doi: 10.18632/oncotarget.28249. eCollection 2022.
Abemaciclib is an oral, selective cyclin-dependent kinase 4 & 6 inhibitor (CDK4 & 6i), approved for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) as monotherapy for endocrine refractory disease, and with endocrine therapy (ET) for initial treatment and after progression on ET. Abemaciclib has also shown clinical activity in combination with ET in patients with high risk early BC (EBC). Here, we examined the preclinical attributes of abemaciclib and other CDK4 & 6i using biochemical and cell-based assays. , abemaciclib preferentially inhibited CDK4 kinase activity versus CDK6, resulting in inhibition of cell proliferation in a panel of BC cell lines with higher average potency than palbociclib or ribociclib. Abemaciclib showed activity regardless of amplification and phosphatidylinositol 3-kinase () gene mutation status. In human bone marrow progenitor cells, abemaciclib showed lower impact on myeloid maturation than other CDK4 & 6i when tested at unbound concentrations similar to those observed in clinical trials. Continuous abemaciclib treatment provided profound inhibition of cell proliferation, and triggered senescence and apoptosis. These preclinical results support the unique efficacy and safety profile of abemaciclib observed in clinical trials.
阿贝西利是一种口服、选择性细胞周期蛋白依赖性激酶 4 和 6 抑制剂（CDK4 和 6i），获批用于激素受体阳性（HR+）、人表皮生长因子受体 2 阴性（HER2-）晚期乳腺癌（ABC）作为内分泌难治性疾病的单药治疗，以及与内分泌治疗（ET）联合用于初始治疗和 ET 进展后。阿贝西利在高危早期乳腺癌（EBC）患者中与 ET 联合也显示出临床活性。在这里，我们使用生化和基于细胞的测定法检查了阿贝西利和其他 CDK4 和 6i 的临床前属性。阿贝西利优先抑制 CDK4 激酶活性而非 CDK6，导致在一系列 BC 细胞系中抑制细胞增殖，其平均效力高于 palbociclib 或 ribociclib。阿贝西利表现出活性，无论扩增和磷脂酰肌醇 3-激酶（PI3K）基因突变状态如何。在人类骨髓祖细胞中，与在临床试验中观察到的相似的未结合浓度下测试时，阿贝西利对髓样成熟的影响低于其他 CDK4 和 6i。连续阿贝西利治疗可显著抑制细胞增殖，并触发衰老和凋亡。这些临床前结果支持在临床试验中观察到的阿贝西利独特的疗效和安全性特征。
