The cyclinD:CDK4/6:Rb axis is dysregulated in a variety of human cancers. Targeting this pathway has proven to be a successful therapeutic approach in ER+ breast cancer. In this study, in vitro and in vivo preclinical breast cancer models were used to investigate the expanded use of the CDK4/6 inhibitor, abemaciclib. Using a panel of 44 breast cancer cell lines, differential sensitivity to abemaciclib was observed and was seen predominately in the luminal ER+/HER2− and ER+/HER2+ subtypes. However, a subset of triple-negative breast cancer (TNBC) cell lines with intact Rb signaling were also found to be responsive. Equivalent levels of tumor growth inhibition were observed in ER+/HER2−, ER+/HER2+ as well as biomarker selected TNBC xenografts in response to abemaciclib. In addition, abemaciclib combined with hormonal blockade and/or HER2-targeted therapy induced significantly improved antitumor activity. CDK4/6 inhibition with abemaciclib combined with antimitotic agents, both in vitro and in vivo, did not antagonize the effect of either agent. Finally, we identified a set of Rb/E2F-regulated genes that consistently track with growth inhibitory response and constitute potential pharmacodynamic biomarkers of response to abemaciclib. Taken together, these data represent a comprehensive analysis of the preclinical activity of abemaciclib, used alone or in combination, in human breast cancer models. The subtypes most likely to respond to abemaciclib-based therapies can be identified by measurement of a specific set of biomarkers associated with increased dependency on cyclinD:CDK4/6:Rb signaling. These data support the clinical development of abemaciclib as monotherapy or as a combination partner in selected ER+/HER2−, HER2+/ER+, and TNBCs. Mol Cancer Ther; 17(5); 897–907. ©2018 AACR.

中文翻译：

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abemaciclib 单独或联合抗有丝分裂和靶向治疗在乳腺癌中的临床前活性

cyclinD:CDK4/6:Rb 轴在多种人类癌症中失调。针对这一途径已被证明是一种成功的 ER+ 乳腺癌治疗方法。在这项研究中，体外和体内临床前乳腺癌模型用于研究 CDK4/6 抑制剂 abemaciclib 的扩大使用。使用一组 44 个乳腺癌细胞系，观察到对 abemaciclib 的不同敏感性，主要见于 luminal ER+/HER2- 和 ER+/HER2+ 亚型。然而，还发现具有完整 Rb 信号的三阴性乳腺癌 (TNBC) 细胞系的一个子集也有反应。在 ER+/HER2-、ER+/HER2+ 以及生物标志物选择的 TNBC 异种移植物中观察到等效水平的肿瘤生长抑制，以响应 abemaciclib。此外，abemaciclib 联合激素阻断和/或 HER2 靶向治疗可显着提高抗肿瘤活性。在体外和体内，使用 abemaciclib 与抗有丝分裂剂联合抑制 CDK4/6 不会拮抗任何一种药物的作用。最后，我们确定了一组 Rb/E2F 调节的基因，这些基因始终跟踪生长抑制反应，并构成对 abemaciclib 反应的潜在药效学生物标志物。总之，这些数据代表了对 abemaciclib 在人类乳腺癌模型中单独或联合使用的临床前活性的综合分析。最有可能对基于 abemaciclib 的疗法有反应的亚型可以通过测量一组特定的生物标志物来确定，这些生物标志物与对 cyclinD:CDK4/6:Rb 信号传导的依赖性增加有关。这些数据支持 abemaciclib 作为单一疗法或作为选定 ER+/HER2-、HER2+/ER+ 和 TNBC 的联合合作伙伴的临床开发。摩尔癌症治疗; 17(5); 897-907。©2018 AACR。