A hallmark of cancer is the dysregulation of the cell cycle. The CDK4/6 inhibitor palbociclib is approved for treating advanced estrogen-receptor-positive breast cancer, but its success is limited by the development of acquired resistance owing to long-term therapy despite promising clinical outcomes. This situation necessitates the development of potential combination strategies. Here, we report that didox, an inhibitor of ribonucleotide reductase in combination with palbociclib, can overcome palbociclib resistance in ER-positive and ER-negative breast cancers. This study shows didox downregulates an element of the cell cycle checkpoint, cyclin D1, accompanied by a reduction in NF-κB activity in vitro and tumor growth inhibition of palbociclib-resistant ER positive breast cancer tumor growth in vivo. Furthermore, didox induces cell cycle arrest at G1 as well as reduces ROS generated by on-target effects of palbociclib on the cell cycle. Our current study also reports that the CCND1 and RRM2 upregulation associated with palbociclib-resistant breast cancers decreases upon ribonucleotide reductase inhibition. Our data present a novel and promising biomarker-driven combination therapeutic approach for the treatment of ER-positive and ER-negative breast cancers that involves the inhibition of the CDK4/6-cyclinD1/pRb cell cycle axis that merits further clinical investigation in human models.
癌症的一个标志是细胞周期失调。CDK4/6抑制剂帕博西尼被批准用于治疗晚期雌激素受体阳性乳腺癌，尽管其临床疗效显著，但长期治疗导致的获得性耐药限制了其应用效果。这一现状迫切需要开发潜在的联合治疗策略。本研究报道，核糖核苷酸还原酶抑制剂地多克与帕博西尼联用，能够克服雌激素受体阳性及阴性乳腺癌对帕博西尼的耐药性。实验表明，地多克可下调细胞周期检查点关键蛋白细胞周期蛋白D1，同时伴随NF-κB活性降低，并在体内抑制帕博西尼耐药性雌激素受体阳性乳腺癌的肿瘤生长。此外，地多克可诱导细胞周期停滞于G1期，并减少帕博西尼对细胞周期靶向作用产生的活性氧。本研究还发现，与帕博西尼耐药乳腺癌相关的CCND1和RRM2基因上调现象在核糖核苷酸还原酶受抑制后显著减弱。我们的数据提出了一种新颖且具有前景的生物标志物驱动联合疗法，通过抑制CDK4/6-细胞周期蛋白D1/pRb细胞周期轴，为治疗雌激素受体阳性及阴性乳腺癌提供了新方向，值得在人体模型中开展进一步临床研究。
Targeting the Cell Cycle, RRM2 and NF-κB for the Treatment of Breast Cancers
肿瘤(癌症)患者之家