Single-Cell Dynamics Determines Response to CDK4/6 Inhibition in Triple-Negative Breast Cancer.
Single-Cell Dynamics Determines Response to CDK4/6 Inhibition in Triple-Negative Breast Cancer.
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DOI：
10.1158/1078-0432.ccr-17-0369
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发表时间：
2017-09-15
期刊：
影响因子：
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通讯作者：
Turner NC
中科院分区：
文献类型：
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作者：
Asghar US;Barr AR;Cutts R;Beaney M;Babina I;Sampath D;Giltnane J;Lacap JA;Crocker L;Young A;Pearson A;Herrera-Abreu MT;Bakal C;Turner NC
三阴性乳腺癌（TNBC）是乳腺癌的一个异质亚组，与不良预后相关。我们评估了 CDK4/6 抑制剂在 TNBC 亚型中的活性，并研究了敏感性机制。在体外和体内测试了一组代表 TNBC 的细胞系的 CDK4/6 敏感性。荧光 CDK2 活性报告基因结合延时成像用于单细胞分析。 TNBC 的管腔雄激素受体 (LAR) 亚型对 CDK4/6 抑制高度敏感，无论是在体外 [p<0.001 LAR vs. basal-like] 还是在体内 MDA-MB-453 LAR 细胞系异种移植物中。 CDK2 活性的单细胞分析表明 LAR 和基底样细胞之间的细胞周期动力学存在差异。 Palbociclib 敏感的 LAR 细胞以低水平的 CDK2 活性退出有丝分裂，进入静止状态，需要 CDK4/6 活性才能重新进入细胞周期。 Palbociclib 耐药的基底样细胞退出有丝分裂，直接进入增殖状态，具有高水平的 CDK2 活性，绕过限制点和 CDK4/6 活性的要求。有丝分裂后 CDK2 的高活性是由细胞周期蛋白 E1 表达的暂时失调驱动的。在 PIK3CA 突变 TNBC 细胞系中，CDK4/6 抑制剂与 PI3 激酶抑制剂具有协同作用，将 CDK4/6 抑制剂的敏感性扩展到其他 TNBC 亚型。细胞周期动力学决定 TNBC 中对 CDK4/6 抑制的反应。 CDK4/6 抑制剂单独或联合使用，是针对 TNBC 特定亚组的新型治疗策略。
Triple negative breast cancer (TNBC) is a heterogeneous subgroup of breast cancer that is associated with poor prognosis. We evaluated the activity of CDK4/6 inhibitors across TNBC subtypes, and investigated the mechanisms of sensitivity. A panel of cell lines representative of TNBC were tested for CDK4/6 sensitivity, in vitro and in vivo. A fluorescent CDK2 activity reporter was used for single cell analysis in conjunction with time-lapse imaging. The luminal androgen receptor (LAR) subtype of TNBC was highly sensitive to CDK4/6 inhibition both in vitro [p<0.001 LAR vs. basal-like] and in vivo in MDA-MB-453 LAR cell line xenografts. Single cell analysis of CDK2 activity demonstrated difference in cell cycle dynamics between LAR and basal-like cells. Palbociclib-sensitive LAR cells exit mitosis with low levels of CDK2 activity, into a quiescent state that requires CDK4/6 activity for cell cycle re-entry. Palbociclib-resistant basal-like cells exit mitosis directly into a proliferative state, with high levels of CDK2 activity, bypassing the restriction point and the requirement for CDK4/6 activity. High CDK2 activity post-mitosis is driven by temporal deregulation of cyclin E1 expression. CDK4/6 inhibitors were synergistic with PI3 kinase inhibitors in PIK3CA mutant TNBC cell lines, extending CDK4/6 inhibitor sensitivity to additional TNBC subtypes. Cell cycle dynamics determines response to CDK4/6 inhibition in TNBC. CDK4/6 inhibitor, alone and in combination, are a novel therapeutic strategy for specific subgroups of TNBC.