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The spliceosome as a target of novel antitumour drugs

Nature Reviews Drug Discovery volume 11, pages 847–859 (2012)Cite this article

Subjects

Key Points

  • Bacterial fermentation products with cytostatic and antitumour activity target components of the basal precursor mRNA (pre-mRNA) splicing machinery.

  • At least some of these drugs achieve their effects by interfering with mechanisms that ensure proper recognition of 3′ splice site sequences by spliceosomal U2 small nuclear ribonucleoprotein (snRNP) particles.

  • Rather than global inhibition of the splicing process, cytostatic drug concentrations induce changes in alternative pre-mRNA splicing and downregulation of genes important for cell cycle and tumour progression.

  • The drugs display significantly more potent effects on cancer cells than on normal cells and retain their activity on multidrug-resistant cells.

  • The drug target splicing factor 3B subunit 1 (SF3B1) is a protein component of U2 snRNP that is frequently mutated in myelodysplasias with ring sideroblasts and in chronic lymphocytic leukaemia.

Abstract

Several bacterial fermentation products and their synthetic derivatives display antitumour activities and bind tightly to components of the spliceosome, which is the complex molecular machinery involved in the removal of introns from mRNA precursors in eukaryotic cells. The drugs alter gene expression, including alternative splicing, of genes that are important for cancer progression. A flurry of recent reports has revealed that genes encoding splicing factors, including the drug target splicing factor 3B subunit 1 (SF3B1), are among the most highly mutated in various haematological malignancies such as chronic lymphocytic leukaemia and myelodysplastic syndromes. These observations highlight the role of splicing factors in cancer and suggest that an understanding of the molecular effects of drugs targeting these proteins could open new perspectives for studies of the spliceosome and its role in cancer progression, and for the development of novel antitumour therapies.

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Figure 1: Spliceosome assembly and catalysis of intron removal.
Figure 2: Examples of regulated alternative splicing events relevant for cancer progression.
Figure 3: Natural antitumour compounds targeting SF3B and their synthetic derivatives.
Figure 4: Molecular effects of the drugs on 3′ splice site recognition and other steps of gene expression.
Figure 5: Recurrent mutations in the drug protein target SF3B1.

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Acknowledgements

We thank P. Cironi, C. López-Otín, P. Potter, V. Quesada, J. Vilardell, T. Webb and members of our laboratory for discussions and comments on the manuscript, and three anonymous reviewers for useful suggestions. Work in our group has been supported by Fundación Botín, Consolider RNAREG, Ministerio de Economía y Competitividad, AGAUR, AICR and EURASNET.

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  1. Sophie Bonnal and Luisa Vigevani: These authors contributed equally to this work.

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  1. Centre de Regulació Genòmica, Dr. Aiguader 88, Barcelona, 08003, Spain

    Sophie Bonnal, Luisa Vigevani & Juan Valcárcel

  2. Universitat Pompeu Fabra, Dr. Aiguader 88, Barcelona, 08003, Spain

    Sophie Bonnal, Luisa Vigevani & Juan Valcárcel

  3. Institució Catalana de Recerca i Estudis Avançats (ICREA), Dr. Aiguader 88, Barcelona, 08003, Spain

    Juan Valcárcel

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  1. Sophie Bonnal
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Bonnal, S., Vigevani, L. & Valcárcel, J. The spliceosome as a target of novel antitumour drugs. Nat Rev Drug Discov 11, 847–859 (2012). https://doi.org/10.1038/nrd3823

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