RNA Splicing as a Therapeutic Target in Cancer

RNA splicing is a nuclear enzymatic process that catalyzes excision of segments of premature messenger RNA (mRNA) and ligation to give rise to mature coding mRNA. Genomic and transcriptomic studies of cancer have revealed that RNA splicing is often dysregulated in cancer due to mutations in genes affecting their splicing in cis , alterations in the components of the splicing machinery in trans , and transcriptional as well as epigenetic alterations that impact cotranscriptional splicing. These observations have motivated a number of efforts to pharmacologically modulate splicing using small molecules that bind, degrade, or modify the RNA splicing machinery as well as oligonucleotides and small molecules that bind mRNA transcripts to modulate their processing. These therapeutic modalities are reviewed here along with early findings from clinical trials evaluating these agents in patients. The vast number of opportunities to alter splicing continues to highlight splicing as an exciting therapeutic target in cancer.