Small Molecule Modulators of Pre-mRNA Splicing in Cancer Therapy

Abstract

Pre-mRNA splicing is a fundamental process in mammalian gene expression and alternative RNA splicing plays a considerable role in generating protein diversity. RNA splicing events are also key to the pathology of numerous diseases, particularly cancers. Some tumors are molecularly addicted to specific RNA splicing isoforms making interference with pre-mRNA processing a viable therapeutic strategy. Several RNA splicing modulators have recently been characterized, some showing promise in preclinical studies. While the targets of most splicing modulators are constitutive RNA processing components, possibly leading to undesirable side effects, selectivity for individual splicing events has been observed. Given the high prevalence of splicing defects in cancer, small molecule modulators of RNA processing represent a potentially promising novel therapeutic strategy in cancer treatment. Here, we review their reported effects, mechanisms, and limitations.

Keywords: cancer therapy; splicing modulators.

Figure 1. Cancer-relevant splicing isoforms

Rectangles represent exons, lines represent introns and red crossed circles represent stop codons. Splicing outcome of the genes listed in this review.

Figure 2. Small molecule splicing modulation specificity and function

Despite targeting of generic splicing factors, small molecule modulators of splicing can have gene-specific effects. Rectangles represent exons and lines represent introns. Complex A of the spliceosome is represented here by U2 snRNA and SF3B1. U2 binds to the branch point and is stabilized by SF3B1. Small splicing modulator molecules bind SF3B1 and alter the splicing of cancer-relevant genes. In this specific example, the splicing modulator SSA binds SF3B1 to promote exon 5 skipping of Cyclin A2 [39]. Cyclin A2 plays a key role in cell cycle regulation and its expression is up-regulated in many types of cancer, including breast and liver [87, 88].