Sette Claudio, Paronetto Maria Paola
Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168 Rome, Italy.
GSTEP-Organoids Core Facility, Fondazione Policlinico Agostino Gemelli IRCCS, 00168 Rome, Italy.
Cancers (Basel). 2022 Apr 4;14(7):1827. doi: 10.3390/cancers14071827.
Alternative pre-mRNA processing enables the production of distinct mRNA and protein isoforms from a single gene, thus greatly expanding the coding potential of eukaryotic genomes and fine-tuning gene expression programs. Splicing is carried out by the spliceosome, a complex molecular machinery which assembles step-wise on mRNA precursors in the nucleus of eukaryotic cells. In the last decade, exome sequencing technologies have allowed the identification of point mutations in genes encoding splicing factors as a recurrent hallmark of human cancers, with higher incidence in hematological malignancies. These mutations lead to production of splicing factors that reduce the fidelity of the splicing process and yield splicing variants that are often advantageous for cancer cells. However, at the same time, these mutations increase the sensitivity of transformed cells to splicing inhibitors, thus offering a therapeutic opportunity for novel targeted strategies. Herein, we review the recent literature documenting cancer-associated mutations in components of the early spliceosome complex and discuss novel therapeutic strategies based on small-molecule spliceosome inhibitors that exhibit strong anti-tumor effects, particularly against cancer cells harboring mutations in spliceosomal components.
可变前体mRNA加工能够从单个基因产生不同的mRNA和蛋白质异构体，从而极大地扩展了真核生物基因组的编码潜力并微调基因表达程序。剪接由剪接体进行，剪接体是一种复杂的分子机器，在真核细胞的细胞核中逐步组装在mRNA前体上。在过去十年中，外显子组测序技术已能够鉴定出编码剪接因子的基因中的点突变，这是人类癌症的一个常见特征，在血液系统恶性肿瘤中发生率更高。这些突变导致剪接因子的产生，这些剪接因子降低了剪接过程的保真度，并产生了通常对癌细胞有利的剪接变体。然而，与此同时，这些突变增加了转化细胞对剪接抑制剂的敏感性，从而为新型靶向策略提供了治疗机会。在此，我们综述了最近记录早期剪接体复合物成分中癌症相关突变的文献，并讨论了基于小分子剪接体抑制剂的新型治疗策略，这些抑制剂具有强大的抗肿瘤作用，特别是对剪接体成分中存在突变的癌细胞。
