Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Blood Disease Institute, Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical University, Xuzhou, China.
Blood. 2023 Jun 8;141(23):2841-2852. doi: 10.1182/blood.2022018885.
Therapeutic targeting of CDK7 has proven beneficial in preclinical studies, yet the off-target effects of currently available CDK7 inhibitors make it difficult to pinpoint the exact mechanisms behind MM cell death mediated by CDK7 inhibition. Here, we show that CDK7 expression positively correlates with E2F and MYC transcriptional programs in cells from patients with multiple myeloma (MM); its selective targeting counteracts E2F activity via perturbation of the cyclin-dependent kinases/Rb axis and impairs MYC-regulated metabolic gene signatures translating into defects in glycolysis and reduced levels of lactate production in MM cells. CDK7 inhibition using the covalent small-molecule inhibitor YKL-5-124 elicits a strong therapeutic response with minimal effects on normal cells, and causes in vivo tumor regression, increasing survival in several mouse models of MM including a genetically engineered mouse model of MYC-dependent MM. Through its role as a critical cofactor and regulator of MYC and E2F activity, CDK7 is therefore a master regulator of oncogenic cellular programs supporting MM growth and survival, and a valuable therapeutic target providing rationale for development of YKL-5-124 for clinical use.
在临床前研究中，靶向细胞周期蛋白依赖性激酶 7（CDK7）已被证明是有益的，然而，目前可用的 CDK7 抑制剂的脱靶效应使得难以确定 CDK7 抑制介导的 MM 细胞死亡的确切机制。在这里，我们表明，CDK7 的表达与多发性骨髓瘤（MM）患者细胞中的 E2F 和 MYC 转录程序呈正相关；其选择性靶向通过干扰细胞周期蛋白依赖性激酶/Rb 轴来拮抗 E2F 活性，并损害 MYC 调节的代谢基因特征，导致 MM 细胞中的糖酵解缺陷和乳酸生成水平降低。使用共价小分子抑制剂 YKL-5-124 抑制 CDK7 会产生强烈的治疗反应，对正常细胞的影响最小，并在包括依赖 MYC 的 MM 的基因工程小鼠模型在内的几种 MM 小鼠模型中引起肿瘤消退，从而提高了几种 MM 小鼠模型的存活率。通过作为 MYC 和 E2F 活性的关键共因子和调节剂的作用，CDK7 因此是支持 MM 生长和存活的致癌细胞程序的主调节因子，是一个有价值的治疗靶点，为 YKL-5-124 的临床应用提供了依据。
Zotero 插件
