Exploiting differential RNA splicing patterns: a potential new group of therapeutic targets in cancer

Abstract

Mutations in genes associated with splicing have been found in hematologic malignancies, but also in solid cancers. Aberrant cancer specific RNA splicing either results from mutations or misexpression of the spliceosome genes directly, or from mutations in splice sites of oncogenes or tumor suppressors. Areas covered: In this review, we present molecular targets of aberrant splicing in various malignancies, information on existing and emerging therapeutics against such targets, and strategies for future drug development. Expert opinion: Alternative splicing is an important mechanism that controls gene expression, and hence pharmacologic and genetic control of aberrant alternative RNA splicing has been proposed as a potential therapy in cancer. To identify and validate aberrant RNA splicing patterns as therapeutic targets we need to (1) characterize the most common genetic aberrations of the spliceosome and of splice sites, (2) understand the dysregulated downstream pathways and (3) exploit in-vivo disease models of aberrant splicing. Antisense oligonucleotides show promising activity, but will benefit from improved delivery tools. Inhibitors of mutated splicing factors require improved specificity, as alternative and aberrant splicing are often intertwined like two sides of the same coin. In summary, targeting aberrant splicing is an early but emerging field in cancer treatment.

Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer

“…Due to the increasing body of evidence pointing toward a strong dysregulation of the splicing process in cancer, many therapeutic strategies to prevent the expression of oncogenic SVs and/or to modulate the activity of the spliceosome have been reported hitherto [42]. In particular, during the last years, many spliceosome inhibitors (e.g.…”

Splicing modulation as novel therapeutic strategy against diffuse malignant peritoneal mesothelioma

“…Based on current data, we now speculate that not only mutations, but also the overexpression of SF3B1 perturbs splicing catalysis and results in the synthesis of pro-tumorigenic splice variants, which may constitute a vulnerability of cancer cells. Splice-switching oligonucleotides and RNA interference are suitable tools to target such variants in vitro [38], however it remains difficult to use these agents in the clinical setting due to limited stability in plasma and intracellular uptake [11]. Therefore we focused on small antitumor molecules targeting SF3b complex based on the assumption that their activity would be more clinically relevant in tumors where the expression of these factors is altered.…”

Genome-Wide Profiling of Prognostic Alternative Splicing Signature in Colorectal Cancer

“…With convincing data in our study that the majority of poor prognostic AS events were positively correlated with the expression of splicing factors in CRC, whereas favorable prognosis AS events were negatively correlated with the expression of splicing factors. It had been known that the process of splicing is regulated precisely by splicing factors through binding to splice-regulatory sequence elements of specific genes ( 31 ). With current knowledge that two main families of splicing factors are the Ser/Arg rich (SR) proteins and the heterogeneous nuclear ribonucleoproteins (hnRNPs) ( 32 ).…”