Therapeutic Targeting of RNA Splicing in Cancer

Abstract

RNA splicing is a key regulatory step in the proper control of gene expression. It is a highly dynamic process orchestrated by the spliceosome, a macro-molecular machinery that consists of protein and RNA components. The dysregulation of RNA splicing has been observed in many human pathologies ranging from neurodegenerative diseases to cancer. The recent identification of recurrent mutations in the core components of the spliceosome in hematologic malignancies has advanced our knowledge of how splicing alterations contribute to disease pathogenesis. This review article will discuss our current understanding of how aberrant RNA splicing regulation drives tumor initiation and progression. We will also review current therapeutic modalities and highlight emerging technologies designed to target RNA splicing for cancer treatment.

Assessment of molecular and morphological dynamics during long-time in vitro cultivation of cryopreserved human ovarian tissue: risk of genetic alterations

“…In the realm of therapeutics, small molecule agents like Pladienolide B and its analogs, which target SF3B1 and analogous splicing factors, are being rigorously investigated for their potential e cacy in treating malignancies characterized by SF3B1 mutations [27,28]. Additionally, in the context of nonsmall cell lung cancer (NSCLC), the use of small molecule inhibitors like H3B-8800, targeting splicing events associated with mutations in splicing factors such as SRSF2, SF3B1, and U2AF1, represents a novel strategy to disrupt the splicing apparatus and attenuate the proliferation of neoplastic cells [29,30].…”

Exploring Splicing Modulation as an Innovative Approach to Combat Pancreatic Cancer: SF3B1 Emerges as a Prognostic Indicator and Therapeutic Target

“…Irregularities in splicing factor genes, encompassing alterations in expression levels or the presence of mutations, have the capacity to produce abnormal mRNA splicing patterns on a genome-wide scale 12 . This phenomenon is a prevalent characteristic observed in various cancer types, spanning from haematological to solid cancers 13 . Numerous splicing factors alterations have been identified in PDAC.…”

Immunomodulatory Gene-Splicing Dysregulation in Tumorigenesis: Unmasking the Complexity

“…There are compounds used for aberrant splicing-related cancers, including GEX1 [ 118 ], spliceostatins, sudemycins, FD-895, E7107 and FR901464, which all act directly on the core spliceosomal component SF3B1, of which accounts for 10% splicing events [ 119 ]. The use of protein arginine methyltransferases (PRMTs) is an attractive approach to targeting splicing.…”

“…The use of protein arginine methyltransferases (PRMTs) is an attractive approach to targeting splicing. They catalyze arginine dimethylation of various substrates, including RBPs and splicing factors [ 118 ]. GSK3368715 and PF06939999, GSK3326595 and JNJ-64619178 are type I and PRMT5 inhibitors currently in clinical trials, respectively.…”