Targeting the transcription cycle and RNA processing in cancer treatment.

The transcriptional program and RNA splicing machinery are highly and frequently dysregulated in human cancers due to genomic and epigenomic alterations during tumorigenesis. This leads to cancer-specific dependencies on components of the transcriptional program and RNA splicing machinery, providing alternative and targetable “Achilles’ heels” for cancer treatment in the clinic. To target these vulnerabilities in cancer cells, potent and specific transcriptional CDK inhibitors and chemical compounds that impair splicing have been developed and evaluated in preclinical cancer models. Several novel combination approaches with immune or targeted therapies have also been proposed for cancer treatment. More recently, inhibitors targeting transcriptional CDKs, splicing, or PRMT5 have shown promising therapeutic potential in preclinical studies, and many of them have rapidly advanced into early clinical trials for treatment of human cancer.

在人类癌症中，由于肿瘤发生过程中的基因组和表观基因组改变，转录程序和RNA剪接机制高度且频繁地失调。这导致癌症对转录程序和RNA剪接机制的组成部分产生特异性依赖，为临床癌症治疗提供了可替代且可靶向的“阿喀琉斯之踵”。为了针对癌细胞中的这些脆弱性，已经开发出有效的特异性转录细胞周期蛋白依赖性激酶（CDK）抑制剂以及损害剪接的化合物，并在癌症临床前模型中进行了评估。还提出了几种与免疫疗法或靶向疗法相结合的新方法用于癌症治疗。最近，靶向转录CDK、剪接或蛋白精氨酸甲基转移酶5（PRMT5）的抑制剂在临床前研究中显示出有前景的治疗潜力，其中许多已迅速进入治疗人类癌症的早期临床试验阶段。