Therapeutic Targeting of Alternative RNA Splicing in Gastrointestinal Malignancies and Other Cancers

Recent comprehensive genomic studies including single-cell RNA sequencing and characterization have revealed multiple processes by which protein-coding and noncoding RNA processing are dysregulated in many cancers. More specifically, the abnormal regulation of mRNA and precursor mRNA (pre-mRNA) proc...

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Autores principales:	Ilyas Sahin, Andrew George, Attila A. Seyhan
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	dysregulation of RNA processing alternative splicing therapeutic targeting of alternative splicing cancer gastrointestinal malignancies Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/096fc75571464c5ca0bc969282845241
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spelling	oai:doaj.org-article:096fc75571464c5ca0bc9692828452412021-11-11T17:14:24ZTherapeutic Targeting of Alternative RNA Splicing in Gastrointestinal Malignancies and Other Cancers10.3390/ijms2221117901422-00671661-6596https://doaj.org/article/096fc75571464c5ca0bc9692828452412021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11790https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Recent comprehensive genomic studies including single-cell RNA sequencing and characterization have revealed multiple processes by which protein-coding and noncoding RNA processing are dysregulated in many cancers. More specifically, the abnormal regulation of mRNA and precursor mRNA (pre-mRNA) processing, which includes the removal of introns by splicing, is frequently altered in tumors, producing multiple different isoforms and diversifying protein expression. These alterations in RNA processing result in numerous cancer-specific mRNAs and pathogenically spliced events that generate altered levels of normal proteins or proteins with new functions, leading to the activation of oncogenes or the inactivation of tumor suppressor genes. Abnormally spliced pre-mRNAs are also associated with resistance to cancer treatment, and certain cancers are highly sensitive to the pharmacological inhibition of splicing. The discovery of these alterations in RNA processing has not only provided new insights into cancer pathogenesis but identified novel therapeutic vulnerabilities and therapeutic opportunities in targeting these aberrations in various ways (e.g., small molecules, splice-switching oligonucleotides (SSOs), and protein therapies) to modulate alternative RNA splicing or other RNA processing and modification mechanisms. Some of these strategies are currently progressing toward clinical development or are already in clinical trials. Additionally, tumor-specific neoantigens produced from these pathogenically spliced events and other abnormal RNA processes provide a potentially extensive source of tumor-specific therapeutic antigens (TAs) for targeted cancer immunotherapy. Moreover, a better understanding of the molecular mechanisms associated with aberrant RNA processes and the biological impact they play might provide insights into cancer initiation, progression, and metastasis. Our goal is to highlight key alternative RNA splicing and processing mechanisms and their roles in cancer pathophysiology as well as emerging therapeutic alternative splicing targets in cancer, particularly in gastrointestinal (GI) malignancies.Ilyas SahinAndrew GeorgeAttila A. SeyhanMDPI AGarticledysregulation of RNA processingalternative splicingtherapeutic targeting of alternative splicingcancergastrointestinal malignanciesBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11790, p 11790 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	dysregulation of RNA processing alternative splicing therapeutic targeting of alternative splicing cancer gastrointestinal malignancies Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	dysregulation of RNA processing alternative splicing therapeutic targeting of alternative splicing cancer gastrointestinal malignancies Biology (General) QH301-705.5 Chemistry QD1-999 Ilyas Sahin Andrew George Attila A. Seyhan Therapeutic Targeting of Alternative RNA Splicing in Gastrointestinal Malignancies and Other Cancers
description	Recent comprehensive genomic studies including single-cell RNA sequencing and characterization have revealed multiple processes by which protein-coding and noncoding RNA processing are dysregulated in many cancers. More specifically, the abnormal regulation of mRNA and precursor mRNA (pre-mRNA) processing, which includes the removal of introns by splicing, is frequently altered in tumors, producing multiple different isoforms and diversifying protein expression. These alterations in RNA processing result in numerous cancer-specific mRNAs and pathogenically spliced events that generate altered levels of normal proteins or proteins with new functions, leading to the activation of oncogenes or the inactivation of tumor suppressor genes. Abnormally spliced pre-mRNAs are also associated with resistance to cancer treatment, and certain cancers are highly sensitive to the pharmacological inhibition of splicing. The discovery of these alterations in RNA processing has not only provided new insights into cancer pathogenesis but identified novel therapeutic vulnerabilities and therapeutic opportunities in targeting these aberrations in various ways (e.g., small molecules, splice-switching oligonucleotides (SSOs), and protein therapies) to modulate alternative RNA splicing or other RNA processing and modification mechanisms. Some of these strategies are currently progressing toward clinical development or are already in clinical trials. Additionally, tumor-specific neoantigens produced from these pathogenically spliced events and other abnormal RNA processes provide a potentially extensive source of tumor-specific therapeutic antigens (TAs) for targeted cancer immunotherapy. Moreover, a better understanding of the molecular mechanisms associated with aberrant RNA processes and the biological impact they play might provide insights into cancer initiation, progression, and metastasis. Our goal is to highlight key alternative RNA splicing and processing mechanisms and their roles in cancer pathophysiology as well as emerging therapeutic alternative splicing targets in cancer, particularly in gastrointestinal (GI) malignancies.
format	article
author	Ilyas Sahin Andrew George Attila A. Seyhan
author_facet	Ilyas Sahin Andrew George Attila A. Seyhan
author_sort	Ilyas Sahin
title	Therapeutic Targeting of Alternative RNA Splicing in Gastrointestinal Malignancies and Other Cancers
title_short	Therapeutic Targeting of Alternative RNA Splicing in Gastrointestinal Malignancies and Other Cancers
title_full	Therapeutic Targeting of Alternative RNA Splicing in Gastrointestinal Malignancies and Other Cancers
title_fullStr	Therapeutic Targeting of Alternative RNA Splicing in Gastrointestinal Malignancies and Other Cancers
title_full_unstemmed	Therapeutic Targeting of Alternative RNA Splicing in Gastrointestinal Malignancies and Other Cancers
title_sort	therapeutic targeting of alternative rna splicing in gastrointestinal malignancies and other cancers
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/096fc75571464c5ca0bc969282845241
work_keys_str_mv	AT ilyassahin therapeutictargetingofalternativernasplicingingastrointestinalmalignanciesandothercancers AT andrewgeorge therapeutictargetingofalternativernasplicingingastrointestinalmalignanciesandothercancers AT attilaaseyhan therapeutictargetingofalternativernasplicingingastrointestinalmalignanciesandothercancers
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Therapeutic Targeting of Alternative RNA Splicing in Gastrointestinal Malignancies and Other Cancers

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