Department of Medicine and Surgery, University of Parma, Parma, Italy.
Biochem Pharmacol. 2019 Dec;170:113676. doi: 10.1016/j.bcp.2019.113676. Epub 2019 Oct 21.
Dysregulation of the cell cycle is a hallmark of cancer that leads to aberrant cellular proliferation. CDK4/6 are cyclin-dependent kinases activated in response to proliferative signaling, which induce RB hyper-phosphorylation and hence activation of E2F transcription factors, thus promoting cell cycle progression through the S phase. Pharmacologic inhibition of CDK4/6 by palbociclib, ribociclib, or abemaciclib has been showing promising activity in multiple cancers with the best results achieved in combination with other agents. Indeed, CDK4/6 inhibitors are currently approved in combination with endocrine therapy for the treatment of estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer. Moreover, a number of clinical trials are currently underway to test the efficacy of combining CDK4/6 inhibitors with different drugs not only in breast but also in other types of cancer. Beyond the inhibition of cell proliferation, CDK4/6 inhibitors have recently revealed new effects on cancer cells and on tumor microenvironment. In particular, it has been reported that these agents induce a senescent-like phenotype, impact on cell metabolism and exert both immunomodulatory and immunogenic effects. Here we describe recent data on the anti-tumor effects of CDK4/6 inhibitors as single agents or in combined therapies, focusing in particular on their metabolic and immunomodulatory activities.
细胞周期失调是癌症的一个标志，导致细胞异常增殖。CDK4/6 是细胞周期蛋白依赖性激酶，可对增殖信号做出反应而被激活，进而诱导 RB 过度磷酸化，从而激活 E2F 转录因子，从而促进细胞周期通过 S 期。通过 palbociclib、ribociclib 或 abemaciclib 抑制 CDK4/6 的药理作用在多种癌症中显示出有希望的活性，与其他药物联合使用时效果最佳。事实上，CDK4/6 抑制剂目前已与内分泌治疗联合用于治疗雌激素受体阳性、人表皮生长因子受体 2 阴性的晚期或转移性乳腺癌。此外，目前正在进行多项临床试验，以测试 CDK4/6 抑制剂与不同药物联合使用的疗效，不仅在乳腺癌中，而且在其他类型的癌症中也是如此。除了抑制细胞增殖外，CDK4/6 抑制剂最近还揭示了对癌细胞和肿瘤微环境的新作用。据报道，这些药物可诱导类似衰老的表型，影响细胞代谢，并发挥免疫调节和免疫原性作用。在这里，我们描述了 CDK4/6 抑制剂作为单一药物或联合治疗的抗肿瘤作用的最新数据，特别关注其代谢和免疫调节活性。
