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

Abstract

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.

Neoantigens: promising targets for cancer therapy

“…Alternative processing of mRNA, including alternative splicing events, polyadenylation (pA), RNA editing and allegedly non-coding regions, contributes to the diversity of tumor-specific neoantigens. 19,81,[114][115][116] Transcript alternative splicing The abnormal alternative mRNA splicing is another potential source of tumor-specific neoantigens. 22,117 RNA splicing process the premature mRNA into mature RNA with high efficiency and fidelity in normal cells.…”

MicroRNA-21 Expression as a Prognostic Biomarker in Oral Cancer: Systematic Review and Meta-Analysis

“…The main genetic alterations affecting carcinogenesis involve changes in tumor suppressors (APC, p53 BRCA2, PTCH, NF1, VHL, Rb BCL2, SWI/SNF, p16, CD95, ST5, YPEL3, ST7, and ST14) and oncogenes (Ras, jun, fas, erbA, abl, raf, gsp, sis, erbB, and fms) in addition the onset and progression of oral cancer involve changes of DNA methylation, histone modifications, and non-coding alterations of RNA, including microRNAs (miRNA) [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ].…”

Genome-wide identification of alternative splicing associated with histone deacetylase inhibitor in cutaneous T-cell lymphomas

“…AS is the process of reconnecting RNA exons produced by the transcription of mRNA precursors for genes via RNA splicing in various ways ( Stamm et al, 2005 ). Abnormal splicing of genes is often observed in oncogenes and tumor-suppressor genes, and promotes tumor occurrence and development ( Kozlovski et al, 2017 ; Sahin et al, 2021 ). HDACi can re-express inhibited regulatory genes in cancer cells and reverse their malignant phenotypes.…”