Aberrant RNA splicing and therapeutic opportunities in cancers

• Published in: Cancer science Vol. 113; no. 2; pp. 373 - 381
• Main Authors: Yamauchi, Hirofumi, Nishimura, Kazuki, Yoshimi, Akihide
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.02.2022; John Wiley and Sons Inc
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; antisense oligonucleotide; Cancer; Gene expression; Humans; Leukemia; Mutation; Mutation hot spots; Neoplasms - drug therapy; Neoplasms - genetics; Oligonucleotides, Antisense - genetics; Oligonucleotides, Antisense - metabolism; Oligonucleotides, Antisense - therapeutic use; Pathogenesis; Proteins; Review; Ribonucleic acid; RNA; RNA binding protein; RNA Splicing - drug effects; RNA Splicing - genetics; RNA Splicing Factors - antagonists & inhibitors; RNA Splicing Factors - genetics; RNA Splicing Factors - metabolism; RNA-Binding Proteins - antagonists & inhibitors; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; SF3b; Spliceosomes - drug effects; Spliceosomes - genetics; Spliceosomes - metabolism; splicing factor; Splicing factors; Transcription; Tumorigenesis; Tumors; cancer; SF3b; antisense oligonucleotide; RNA binding protein; splicing factor
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15213

There has been accumulating evidence that RNA splicing is frequently dysregulated in a variety of cancers and that hotspot mutations affecting key splicing factors, SF3B1, SRSF2 and U2AF1, are commonly enriched across cancers, strongly suggesting that aberrant RNA splicing is a new class of hallmark that contributes to the initiation and/or maintenance of cancers. In parallel, some studies have demonstrated that cancer cells with global splicing alterations are dependent on the transcriptional products derived from wild‐type spliceosome for their survival, which potentially creates a therapeutic vulnerability in cancers with a mutant spliceosome. It has been c. 10 y since the frequent mutations affecting splicing factors were reported in cancers. Based on these surprising findings, there has been a growing interest in targeting altered splicing in the treatment of cancers, which has promoted a wide variety of investigations including genetic, molecular and biological studies addressing how altered splicing promotes oncogenesis and how cancers bearing alterations in splicing can be targeted therapeutically. In this mini‐review we present a concise trajectory of what has been elucidated regarding the pathogenesis of cancers with aberrant splicing, as well as the development of therapeutic strategies to target global splicing alterations in cancers. Transcription and pre‐mRNA splicing are key steps in the control of gene expression in eukaryotic cells and mutations in genes regulating each of these processes are common in cancers. By reviewing the recent advances in this field, we described the pathogenic mechanisms in which the hotspot mutations in genes encoding splicing factors drive oncogenesis, and therapeutic strategies for targeting global alterations in splicing, including the use of splicing modulators, inhibition of splicing regulatory proteins, emerging technologies using antisense oligonucleotides and a potential tactic to improve the response to checkpoint blockade.