Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California.
Cancer Discov. 2020 Mar;10(3):351-370. doi: 10.1158/2159-8290.CD-19-0528. Epub 2020 Feb 18.
Drugs targeting the cell cycle-regulatory cyclin-dependent kinase (CDK) 4 and 6 have been approved for the treatment of hormone receptor-positive breast cancer, and inhibitors targeting other cell-cycle CDKs are currently in clinical trials. Another class of CDKs, the transcription-associated CDKs, including CDK7, CDK8, CDK9, CDK12 and CDK13, are critical regulators of gene expression. Recent evidence suggests several novel functions of these CDKs, including regulation of epigenetic modifications, intronic polyadenylation, DNA-damage responses, and genomic stability. Here, we summarize our current understanding of the transcriptional CDKs, their utility as biomarkers, and their potential as therapeutic targets. SIGNIFICANCE: CDK inhibitors targeting CDK4 and CDK6 have been approved in hormone receptor-positive breast cancer, and inhibitors targeting other cell-cycle CDKs are currently in clinical trials. Several studies now point to potential therapeutic opportunities by inhibiting the transcription-associated CDKs as well as therapeutic vulnerabilities with PARP inhibitors and immunotherapy in tumors deficient in these CDKs.
靶向细胞周期调节细胞周期蛋白依赖性激酶 (CDK) 4 和 6 的药物已被批准用于治疗激素受体阳性乳腺癌，而靶向其他细胞周期 CDK 的抑制剂目前正在临床试验中。另一类 CDK，即转录相关 CDK，包括 CDK7、CDK8、CDK9、CDK12 和 CDK13，是基因表达的关键调节剂。最近的证据表明这些 CDK 具有几种新的功能，包括调节表观遗传修饰、内含子多聚腺苷酸化、DNA 损伤反应和基因组稳定性。在这里，我们总结了我们对转录 CDK 的现有认识，包括它们作为生物标志物的用途及其作为治疗靶点的潜力。意义：靶向 CDK4 和 CDK6 的 CDK 抑制剂已在激素受体阳性乳腺癌中获得批准，而靶向其他细胞周期 CDK 的抑制剂目前正在临床试验中。几项研究现在指出，通过抑制转录相关 CDK 以及在这些 CDK 缺失的肿瘤中使用 PARP 抑制剂和免疫疗法可能会带来治疗机会和治疗弱点。
