Tibes Raoul, Bogenberger James M
NYU School of Medicine & Perlmutter Cancer Center, NYU Langone Health, New York, NY, United States.
Mayo Clinic, Scottsdale, AZ, United States.
Front Oncol. 2019 Dec 12;9:1205. doi: 10.3389/fonc.2019.01205. eCollection 2019.
Acute myeloid leukemia (AML) is the most common adult acute leukemia. Survival remains poor, despite decades of scientific advances. Cytotoxic induction chemotherapy regimens are standard-of-care for most patients. Many investigations have highlighted the genomic heterogeneity of AML, and several new targeted therapeutic options have recently been approved. Additional novel therapies are showing promising clinical results and may rapidly transform the therapeutic landscape of AML. Despite the emerging clinical success of B-cell lymphoma (BCL)-2 targeting in AML and a large body of preclinical data supporting myeloid leukemia cell (MCL)-1 as an attractive therapeutic target for AML, MCL-1 targeting remains relatively unexplored, although novel MCL-1 inhibitors are under clinical investigation. Inhibitors of cyclin-dependent kinases (CDKs) involved in the regulation of transcription, CDK9 in particular, are being investigated in AML as a strategy to target MCL-1 indirectly. In this article, we review the basis for CDK inhibition in oncology with a focus on relevant preclinical mechanism-of-action studies of CDK9 inhibitors in the context of their therapeutic potential specifically in AML.
急性髓系白血病（AML）是最常见的成人急性白血病。尽管有几十年的科学进展，但其生存率仍然很低。细胞毒性诱导化疗方案是大多数患者的标准治疗方法。许多研究强调了AML的基因组异质性，最近有几种新的靶向治疗选择获得批准。其他新型疗法也显示出有前景的临床结果，可能会迅速改变AML的治疗格局。尽管针对AML的B细胞淋巴瘤（BCL）-2靶向治疗在临床上取得了新的成功，并且有大量临床前数据支持髓系白血病细胞（MCL）-1作为AML的一个有吸引力的治疗靶点，但尽管新型MCL-1抑制剂正在进行临床研究，MCL-1靶向治疗仍相对未被探索。参与转录调控的细胞周期蛋白依赖性激酶（CDK）抑制剂，特别是CDK9，正在AML中作为间接靶向MCL-1的一种策略进行研究。在本文中，我们回顾了肿瘤学中CDK抑制的基础，重点关注CDK9抑制剂在AML治疗潜力背景下的相关临床前作用机制研究。
