Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
Instituto Português de Oncologia de Lisboa, Serviço de Hematologia, Lisboa, Portugal.
Nat Rev Drug Discov. 2020 Feb;19(2):112-129. doi: 10.1038/s41573-019-0042-3. Epub 2019 Sep 25.
Discoveries in the past decade have highlighted the potential of mRNA as a therapeutic target for cancer. Specifically, RNA sequencing revealed that, in addition to gene mutations, alterations in mRNA can contribute to the initiation and progression of cancer. Indeed, precursor mRNA processing, which includes the removal of introns by splicing and the formation of 3' ends by cleavage and polyadenylation, is frequently altered in tumours. These alterations result in numerous cancer-specific mRNAs that generate altered levels of normal proteins or proteins with new functions, leading to the activation of oncogenes or the inactivation of tumour-suppressor genes. Abnormally spliced and polyadenylated mRNAs are also associated with resistance to cancer treatment and, unexpectedly, certain cancers are highly sensitive to the pharmacological inhibition of splicing. This Review summarizes recent progress in our understanding of how splicing and polyadenylation are altered in cancer and highlights how this knowledge has been translated for drug discovery, resulting in the production of small molecules and oligonucleotides that modulate the spliceosome and are in clinical trials for the treatment of cancer.
在过去十年中，人们发现了 mRNA 作为癌症治疗靶点的潜力。具体来说，RNA 测序表明，除了基因突变外，mRNA 的改变也可能导致癌症的发生和发展。事实上，在前体 mRNA 加工过程中，包括通过剪接去除内含子和通过切割和多聚腺苷酸化形成 3' 末端，在肿瘤中经常发生改变。这些改变导致了许多癌症特异性的 mRNA，这些 mRNA 产生了正常蛋白或具有新功能的蛋白的改变水平，导致癌基因的激活或肿瘤抑制基因的失活。异常剪接和多聚腺苷酸化的 mRNA 也与癌症治疗的耐药性有关，出人意料的是，某些癌症对剪接的药理学抑制非常敏感。这篇综述总结了我们对癌症中剪接和多聚腺苷酸化改变的理解的最新进展，并强调了如何将这些知识转化为药物发现，从而产生了调节剪接体的小分子和寡核苷酸，并正在进行临床试验以治疗癌症。
