Targeting the spliceosome to treat MYC-driven cancers

MYC overexpression or hyperactivation is a well known driver of human cancer. Despite being the subject of intense study for many years, attempts to therapeutically inhibit MYC directly have been unsuccessful, making synthetic lethal strategies attractive. MYC is a transcription factor, and indeed its oncogenic activity is attributed to its prominent role in gene expression. However, whilst increased production of RNA, and thereby proteins, may enable cancer cell growth, there is a resultant burden on these cells to process all this RNA. Last month, Hsu et al. reported that the spliceosome, which is required for processing of precursor mRNA to mature mRNA, is a target of oncogenic stress in MYC-driven cancers.1 They identified components of the core spliceosome which are synthetically lethal with MYC activation and showed that genetic or pharmacological inhibition of these spliceosomal factors impaired survival of MYC-dependent breast cancers.

In a genome-wide MYC-synthetic lethal screen performed previously, BUD31 was identified as a MYC-synthetic lethal gene.2 While in yeast BUD31 had been linked to the spliceosome, its function in mammalian systems had yet to be determined. Using co-immunoprecipitation and bimolecular fluorescence complementation experiments it was shown that BUD31 associates with 79 of the 134 core spliceosomal components, which are involved in a variety of the major spliceosomal subcomplexes, inferring that it is present at several stages of spliceosomal assembly. Furthermore, knockdown experiments indicated that loss of BUD31 significantly inhibited pre-mRNA splicing and led to defects in early spliceosome assembly. It appears therefore that mammalian BUD31 functions as a core spliceosomal protein.

Accordingly the authors suggest that cells with oncogenic MYC require BUD31 for survival due to this role in the spliceosome. Indeed it was shown that if BUD31 is unable to associate with the spliceosome, the proliferation of MYC-driven cancer cells is significantly inhibited. Other components of the spliceosome assembly were consequently examined. It was found that partial depletion of all the components studied led to loss of cell viability and increased apoptosis of MYC-hyperactivated cells. One of these components was SF3B1 (splicing factor 3b, subunit 1). To test whether pharmacological inhibition of the spliceosome is synthetically lethal with MYC, SD6 was developed as a bioavailable small molecule inhibitor of SF3B1.3 Low (10-20 nM) concentrations of SD6 were able to selectively suppress colony formation and induce apoptosis of MYC-hyperactivated cells.

By comparing intron retention (IR) after BUD31 knockdown in MYC-normal or MYC-hyperactivated cells it was shown that in combination MYC activation and partial spliceosome inhibition result in increased IR. This indicates that the MYC-induced increase in mRNA synthesis increases cellular dependency on the spliceosome. Moreover, depletion of BUD31 caused a considerably larger decrease in cellular polyadenylated mRNA following inhibition of transcription in MYC-hyperactivated cells than in control cells, indicative of defects in pre-mRNA maturation and stability.

Finally the authors queried whether MYC-driven breast cancers exhibit increased sensitivity to knockdown of spliceosomal genes. A pronounced correlation was observed between MYC-dependency and spliceosome-dependency in basal breast cancer lines. In one example the effects of genetic and pharmacological inhibition of the spliceosome were tested on MYC-dependent metastatic triple-negative breast cancer (TNBC) models. Use of BUD31 or SF3B1 shRNA reduced cell viability and the TNBC cells were significantly more sensitive (IC50 ≈ 4nM) to treatment with inhibitor SD6 than were MYC-normal cell lines (IC50 ≈ 53nM). Overall the results suggested that MYC-driven breast cancers are more highly dependent on the spliceosome.

This study clearly highlights targeting of the core spliceosome as a promising strategy for treatment of MYC-driven cancers and explains the basis for the synthetic lethality of BUD31 and MYC.

  1. Hsu, T. Y.-T. et al. The spliceosome is a therapeutic vulnerability in MYC-driven cancer. Nature 525, 384–388 (2015).
  2. Kessler, J. D. et al. A sumoylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science 335, 348–353 (2012).
  3. Lagisetti, C. et al. Optimization of antitumor modulators of pre-mRNA splicing. J. Med. Chem. 56, 10033–10044 (2013).

Blog written by: Katie Duffell


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