Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) were designed to induce cancer cell cycle arrest. Recent studies have suggested that these agents also exert other effects, influencing cancer cell immunogenicity, apoptotic responses and differentiation. Using cell-based and mouse models of breast cancer together with clinical specimens, we show that CDK4/6 inhibitors induce remodeling of cancer cell chromatin characterized by widespread enhancer activation, and that this explains many of these effects. The newly activated enhancers include classical super-enhancers that drive luminal differentiation and apoptotic evasion, as well as a set of enhancers overlying endogenous retroviral elements that are enriched for proximity to interferon-driven genes. Mechanistically, CDK4/6 inhibition increases the level of several activator protein-1 transcription factor proteins, which are in turn implicated in the activity of many of the new enhancers. Our findings offer insights into CDK4/6 pathway biology and should inform the future development of CDK4/6 inhibitors.

细胞周期蛋白依赖性激酶 4 和 6 (CDK4/6) 的药理学抑制剂旨在诱导癌细胞周期停滞。最近的研究表明，这些药物还发挥其他作用，影响癌细胞的免疫原性、凋亡反应和分化。使用基于细胞和小鼠的乳腺癌模型以及临床标本，我们发现 CDK4/6 抑制剂可诱导癌细胞染色质的重塑，其特征是广泛的增强子激活，这解释了其中的许多作用。新激活的增强子包括驱动管腔分化和凋亡逃避的经典超级增强子，以及一组覆盖内源性逆转录病毒元件的增强子，这些元件因接近干扰素驱动的基因而富集。机械地，CDK4/6 抑制增加了几种激活蛋白-1 转录因子蛋白的水平，这些蛋白又与许多新增强子的活性有关。我们的研究结果提供了对 CDK4/6 通路生物学的见解，并应为 CDK4/6 抑制剂的未来发展提供信息。