Abstract
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.
Key points
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Alternative splicing enables the generation of distinct mRNA and protein isoforms from a single gene. Splicing is carried out by the spliceosome, one of the most complex molecular machineries of eukaryotic cells.
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Splicing perturbations are common in cancer and are associated with mutations in and/or altered expression of the components of the splicing machinery.
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Splicing perturbations contribute to every hallmark of cancer and can generate neoantigens relevant to the design of cancer vaccines and other immunotherapies.
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Cancer cells generate advantageous splicing variants, at the cost of reducing the efficiency or fidelity of the splicing process, thus conferring a special susceptibility to splicing inhibitors and providing a therapeutic window for targeting the splicing process.
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Small-molecule modulators of the spliceosome have demonstrated antitumour effects and are particularly active against cancer cells harbouring mutations in spliceosomal components.
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Antisense oligonucleotides offer promise to modulate cancer-relevant alternative splicing decisions, with proof of concept for this type of therapy demonstrated by Nusinersen, a first-in-class treatment for patients with spinal muscular atrophy.
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Acknowledgements
The authors thank Dolors Colomer, Armando López-Guillermo and members of their laboratory for critical reading of the manuscript, and Adrian Krainer, Omar Abdel-Wahab and Rotem Karni for their constructive critique during the review process. I.L.-O. is a recipient of a Severo Ochoa PhD4MD Program Fellowship. The work of the authors is supported by the European Research Council, Worldwide Cancer Research, the Spanish Ministry of Economy and Competitiveness, the Agència de Gestió d’Ajuts Universitaris i de Recerca, and the Centre of Excellence Severo Ochoa Award (to the Centre for Genomic Regulation of the Barcelona Institute of Science and Technology).
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Bonnal, S.C., López-Oreja, I. & Valcárcel, J. Roles and mechanisms of alternative splicing in cancer — implications for care. Nat Rev Clin Oncol 17, 457–474 (2020). https://doi.org/10.1038/s41571-020-0350-x
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DOI: https://doi.org/10.1038/s41571-020-0350-x
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