PDF(Pubmed)
Abstract：
Inhibitors of Bruton\'s tyrosine kinase (BTKi) and chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 are paradigm-shifting advances in treating patients with aggressive mantle cell lymphoma (MCL). However, clinical relapses following BTKi and CD19-directed CAR-T treatments are a fast-growing medical challenge. Development of novel therapies to overcome BTKi resistance (BTKi-R) and BTKi-CAR-T dual resistance (Dual-R) are urgently needed. Our single-cell RNA sequencing data revealed major transcriptomic reprogramming, with great enrichment of MYC-targets evolving as resistance to these therapies developed. Interestingly, cyclin-dependent kinase 9 (CDK9), a critical component of the positive transcription elongation factor-b complex, was among the top upregulated genes in Dual-R vs. BTKi-R samples. We therefore hypothesized that targeting CDK9 may turn off MYC-driven tumor survival and drug resistance. Enitociclib (formerly VIP152) is a selective CDK9 inhibitor whose potency against MCL has not been assessed. In this study, we found that enitociclib was highly potent in targeting lymphoma cells, with the half-maximal inhibitory concentration (IC50) ranging from 32 to 172 nM in MCL and diffuse large B-cell lymphoma cell lines. It inhibited CDK9 phosphorylation and downstream events including de novo synthesis of the short-lived proteins c-MYC, MCL-1, and cyclin D1, and induced apoptosis in a caspase-3-dependent manner. Enitociclib potently inhibited in vivo tumor growth of cell line-derived and patient-derived xenografts having therapeutic resistance. Our data demonstrate the potency of enitociclib in overcoming therapeutic resistance in MCL models and provide evidence in favor of its clinical investigation.
摘要：
布鲁顿酪氨酸激酶（BTKi）抑制剂和针对CD19的嵌合抗原受体T细胞（CAR-T）疗法是治疗侵袭性套细胞淋巴瘤（MCL）患者的范式转变。然而,BTKi和CD19定向CAR-T治疗后的临床复发是一个快速增长的医学挑战.迫切需要开发克服BTKi抗性(BTKi-R)和BTKi-CAR-T双重抗性(Dual-R)的新疗法。我们的单细胞RNA测序数据揭示了主要的转录组重编程，随着对这些疗法的耐药性的发展，MYC靶标的极大丰富。有趣的是,细胞周期蛋白依赖性激酶9（CDK9），正转录延伸因子-b复合物的关键组成部分，在Dual-R与BTKi-R样品。因此，我们假设靶向CDK9可能会关闭MYC驱动的肿瘤存活和耐药性。Enitociclib（以前称为VIP152）是一种选择性CDK9抑制剂，尚未评估其抗MCL的效力。在这项研究中,我们发现enitociclib在靶向淋巴瘤细胞方面非常有效，在MCL和弥漫性大B细胞淋巴瘤细胞系中，半数最大抑制浓度（IC50）为32至172nM。它抑制CDK9磷酸化和下游事件，包括从头合成的短寿命蛋白c-MYC，MCL-1和细胞周期蛋白D1，并以caspase-3依赖性方式诱导细胞凋亡。Enitociclib有效抑制具有治疗抗性的细胞系来源和患者来源的异种移植物的体内肿瘤生长。我们的数据证明了enitociclib在克服MCL模型中的治疗抗性方面的效力，并提供了有利于其临床研究的证据。
