Targeting mRNA processing as an anticancer strategy

Abstract

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.