Development of Anticancer Drugs Targeting Aberrant Splicing and Nonsense-Mediated mRNA Decay

In eukaryotes, mRNA precursors transcribed from DNA undergo RNA splicing and are converted into mature mRNA. In recent years, the progression from DNA microarrays to next-generation sequencing has allowed the detection and analysis of mRNA splicing abnormalities. This has revealed aberrant cis- and trans-type mRNA splicing in some cancer cells, which is considered a promising target for anticancer drugs. Eukaryotic cells have a quality control mechanism called nonsense-mediated mRNA decay (NMD) that degrades mRNAs with nonsense mutations and maintains cellular homeostasis. NMD also eliminates abnormally spliced mRNAs in tumor cells; mRNA that differ from the splicing patterns in normal cells. When analyzing splicing abnormalities with next-generation sequencers, NMD must be considered. In this review, we provide an overview of splicing aberrations in quality control mechanisms and explain the current status and prospects of anticancer drugs targeting these aberrations. We foresee the commercialization of anticancer drug seeds targeting splicing defects. An example of these is NMD inhibitors, which not only disrupt cancer cell homeostasis and induce cell death but can also induce neoantigen expression, suggesting that their combination with immunotherapies may be a potent therapeutic approach.