Molecular Pathways: Understanding and Targeting Mutant Spliceosomal Proteins.

Splicing of precursor messenger RNA is a critical step in regulating gene expression, and major advances are being made in understanding the composition and structure of the enzymatic complex that performs splicing, which is termed the "spliceosome." In parallel, there has been increased appreciation for diverse mechanisms by which alterations in splicing contribute to cancer pathogenesis. Key among these include change-of-function mutations in genes encoding spliceosomal proteins. Such mutations are among the most common genetic alterations in myeloid and lymphoid leukemias, making efforts to therapeutically target cells bearing these mutations critical. To this end, recent studies have clarified that pharmacologic modulation of splicing may be preferentially lethal for cells bearing spliceosomal mutations and may also have a role in the therapy of MYC-driven cancers. This has culminated in the initiation of a clinical trial of a novel oral spliceosome modulatory compound targeting the SF3B complex, and several novel alternative approaches to target splicing are in development as reviewed here. There is now, therefore, a great need to understand the mechanistic basis of altered spliceosomal function in cancers and to study the effects of spliceosomal modulatory compounds in preclinical settings and in well-designed clinical trials. Clin Cancer Res; 23(2); 336-41. ©2016 AACR.