PDF(Pubmed)
Abstract：
This study examines the biological effects of palbociclib and ribociclib in hormone receptor-positive breast cancer, pivotal to the HARMONIA prospective phase III clinical trial. We explore the downstream impacts of these CDK4/6 inhibitors, focusing on cell lines and patient-derived tumor samples. We treated HR+ breast cancer cell lines (T47D, MCF7, and BT474) with palbociclib or ribociclib (100 nM or 500 nM), alone or combined with fulvestrant (1 nM), over periods of 24, 72, or 144 h. Our assessments included PAM50 gene expression, RB1 phosphorylation, Lamin-B1 protein levels, and senescence-associated β-galactosidase activity. We further analyzed PAM50 gene signatures from the CORALLEEN and NeoPalAna phase II trials. Both CDK4/6 inhibitors similarly inhibited proliferation across the cell lines. At 100 nM, both drugs partially reduced p-RB1, with further decreases at 500 nM over 144 h. Treatment led to reduced Lamin-B1 expression and increased senescence-associated β-galactosidase activity. Both drugs enhanced Luminal A and reduced Luminal B and proliferation signatures at both doses. However, the HER2-enriched signature significantly diminished only at the higher dose of 500 nM. Corresponding changes were observed in tumor samples from the CORALLEEN and NeoPalAna studies. At 2 weeks of treatment, both drugs significantly reduced the HER2-enriched signature, but at surgery, this reduction was consistent only with ribociclib. Our findings suggest that while both CDK4/6 inhibitors effectively modulate key biological pathways in HR+/HER2- breast cancer, nuances in their impact, particularly on the HER2-enriched signature, are dose-dependent, influenced by the addition of fulvestrant and warrant further investigation.
摘要：
这项研究检查了palbociclib和ribociclib在激素受体阳性乳腺癌中的生物学效应。和谐前瞻性III期临床试验的关键。我们探索了这些CDK4/6抑制剂的下游影响，专注于细胞系和患者来源的肿瘤样本。我们治疗了HR+乳腺癌细胞系(T47D，MCF7和BT474）与palbociclib或ribociclib（100nM或500nM），单独或与氟维司群(1nM)合用，在24、72或144小时的时间内。我们的评估包括PAM50基因表达，RB1磷酸化，Lamin-B1蛋白水平，和衰老相关的β-半乳糖苷酶活性。我们进一步分析了来自CORALLEEN和NeoPalAnaII期试验的PAM50基因特征。两种CDK4/6抑制剂类似地抑制跨细胞系的增殖。在100nM时，两种药物均部分降低了p-RB1，并在144小时内在500nM时进一步降低。治疗导致Lamin-B1表达降低，衰老相关的β-半乳糖苷酶活性增加。两种药物在两种剂量下都增强了管腔A并减少了管腔B和增殖特征。然而,HER2富集特征仅在500nM的较高剂量下显着减少。在来自CORALLEEN和NeoPalAna研究的肿瘤样品中观察到相应的变化。治疗2周后,两种药物都显著降低了HER2富集的特征，但在手术中,这种减少仅与ribociclib一致。我们的研究结果表明，虽然两种CDK4/6抑制剂都能有效调节HR+/HER2-乳腺癌的关键生物学途径，影响的细微差别，特别是在HER2富集的签名上，是剂量依赖性的，受添加氟维司群的影响，值得进一步调查。
