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  • Review Article
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Targeting mRNA processing as an anticancer strategy

Nature Reviews Drug Discovery volume 19, pages 112–129 (2020)Cite this article

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Abstract

Discoveries in the past decade have highlighted the potential of mRNA as a therapeutic target for cancer. Specifically, RNA sequencing revealed that, in addition to gene mutations, alterations in mRNA can contribute to the initiation and progression of cancer. Indeed, precursor mRNA processing, which includes the removal of introns by splicing and the formation of 3′ ends by cleavage and polyadenylation, is frequently altered in tumours. These alterations result in numerous cancer-specific mRNAs that generate altered levels of normal proteins or proteins with new functions, leading to the activation of oncogenes or the inactivation of tumour-suppressor genes. Abnormally spliced and polyadenylated mRNAs are also associated with resistance to cancer treatment and, unexpectedly, certain cancers are highly sensitive to the pharmacological inhibition of splicing. This Review summarizes recent progress in our understanding of how splicing and polyadenylation are altered in cancer and highlights how this knowledge has been translated for drug discovery, resulting in the production of small molecules and oligonucleotides that modulate the spliceosome and are in clinical trials for the treatment of cancer.

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Fig. 1: Co-transcriptional precursor mRNA processing.
Fig. 2: Mechanisms of precursor mRNA splicing.
Fig. 3: Cleavage and polyadenylation of precursor mRNA.
Fig. 4: Mechanism of action of therapeutic antisense oligonucleotides on precursor mRNA processing.

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Acknowledgements

The authors acknowledge funding from Fundação para a Ciência e Tecnologia and FEDER/POR Lisboa 2020 — Programa Operacional Regional de Lisboa, PORTUGAL 2020 (LISBOA-01–0145-FEDER-016394; 007391).

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Authors and Affiliations

  1. Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal

    Joana Desterro, Pedro Bak-Gordon & Maria Carmo-Fonseca

  2. Instituto Português de Oncologia de Lisboa, Serviço de Hematologia, Lisboa, Portugal

    Joana Desterro

Authors
  1. Joana Desterro
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  2. Pedro Bak-Gordon
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  3. Maria Carmo-Fonseca
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Contributions

J.D. and M.C.-F. contributed equally to all aspects of the article. P.B.-G. researched data for the article and reviewed and edited the manuscript before submission.

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Correspondence to Maria Carmo-Fonseca.

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Related links

Global Cancer Observatory: http://gco.iarc.fr/today/fact-sheets-cancers

MiSplice: https://github.com/ding-lab/misplice

Glossary

7-Methylguanosine cap

A methylated guanosine residue added to the 5′ end of newly synthesized precursor mRNAs. This 5′ cap is necessary for mRNA translation and may also contribute to splicing and the nuclear export of mRNA.

Intron lariat

During the first step of splicing, the 5′ end of the intron is cleaved and the cut end forms a 2′,5′-phosphodiester bond with the branch-point adenosine, resulting in a looped structure known as a lariat.

Heterogeneous nuclear ribonucleoprotein (hnRNP) family

The hnRNP family is composed of numerous proteins that bind to nascent transcripts; they participate in precursor mRNA splicing, help stabilize mRNAs during transport from the nucleus to the cytoplasm and control mRNA translation.

Replication-dependent histones

mRNAs encoding the cell cycle-regulated, replication-dependent histone mRNAs are the only known eukaryotic mRNAs without a poly(A) tail at the 3′ end. Metazoan cells additionally contain replication-independent histone genes that are transcribed into polyadenylated mRNAs.

Nonsense-mediated decay

A mechanism that eliminates mRNAs containing premature translation-termination codons (PTCs). It is intimately linked with splicing, with PTCs often generated by either alternative or aberrant (cryptic) splicing.

Myelodysplastic syndrome

A heterogeneous group of clonal, acquired haematological disorders characterized by ineffective haematopoiesis resulting in peripherical blood cytopenias. Patients with myelodysplastic syndrome carry a variable risk of progression to acute myeloid leukaemia.

Driver mutations

Some spontaneous mutations confer a selective advantage to a cell, leading to cancer. Driver mutations are under positive selection within a population of cancer cells; mutations that are not selectively advantageous to the cell are called ‘passenger mutations’.

The Warburg effect

This effect refers to the observation that cancer cells metabolize glucose preferentially via aerobic glycolysis, rather than by oxidative phosphorylation. Aerobic glycolysis is promoted by PKM2, which is produced by alternative splicing.

Immune tolerance

A state of unresponsiveness to an antigen or a group of antigens that has the potential to induce an immune response. Although genetic alterations in cancers generate neoantigens that could be used by the immune system to distinguish tumour cells from their normal counterparts, tumours acquire immune resistance by co-pting certain immune-checkpoint pathways.

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Desterro, J., Bak-Gordon, P. & Carmo-Fonseca, M. Targeting mRNA processing as an anticancer strategy. Nat Rev Drug Discov 19, 112–129 (2020). https://doi.org/10.1038/s41573-019-0042-3

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