Defining the role of SF3B1K700E mutations in ER+ breast cancer

Abstract

Mutations in SF3B1, a component of the RNA splicing machinery, underpin a number of aggressive cancers. Hotspot mutations in SF3B1 are present in around 3% of breast cancers, are enriched in oestrogen receptor positive disease, and are associated with a poor prognosis. Investigation identified an enrichment of SF3B1K700E binding with Era, aberrant splicing of ER target genes, and a global rewiring of ERA chromatin binding in SF3B1K700E breast cancer cells which suggest these cells are in a primed state to develop resistance to endocrine therapies. To investigate the functional consequences of the SF3B1K700E mutation, a synthetic lethal gene silencing screen was utilised which identified tumour suppressor like genes that could be contributing to SF3B1K700E tumorigenesis, such as BRD9. In addition, a high throughput drug screen was utilised to identify novel therapeutic options for patients with SF3B1K700E mutant cancers. This identified the PARP inhibitor, talazoparib, to selectively kill SF3B1K700E cells. Further interactome analysis identified increased interactions of PARP1, the FACT complex, SF3B1K700E, and H3K4me3. This is suggestive of an adaption of the co-transcriptional splicing program to the burden of the hotspot SF3B1K700E mutation. Indeed, this could be exploited utilising PARP and FACT complex inhibitor combination treatment that synergise in SF3B1K700E cells. In summary, this thesis research has identified a possible rationale for SF3B1K700E enrichment in ER+ breast cancers and a therapeutic strategy for patients with talazoparib (approved in TNBC) and FACT complex inhibitors (in phase I clinical trials).