Roles and mechanisms of alternative splicing in cancer — implications for care

Removal of introns from messenger RNA precursors (pre-mRNA splicing) is an essential step for the expression of most eukaryotic genes. Alternative splicing enables the regulated generation of multiple mRNA and protein products from a single gene. Cancer cells have general as well as cancer type-specific and subtype-specific alterations in the splicing process that can have prognostic value and contribute to every hallmark of cancer progression, including cancer immune responses. These splicing alterations are often linked to the occurrence of cancer driver mutations in genes encoding either core components or regulators of the splicing machinery. Of therapeutic relevance, the transcriptomic landscape of cancer cells makes them particularly vulnerable to pharmacological inhibition of splicing. Small-molecule splicing modulators are currently in clinical trials and, in addition to splice site-switching antisense oligonucleotides, offer the promise of novel and personalized approaches to cancer treatment. Alternative splicing enables the regulated generation of multiple mRNA and protein products from a single gene. This Review outlines the splicing process and its alterations in cancer before highlighting related opportunities for the development of innovative therapeutic approaches.