Hotspot SF3B1 mutations determine response to PARP inhibitors

ABSTRACT: Hotspot mutations in the spliceosomal component gene SF3B1 underpin a number of cancers and have a neomorphic function leading to global disruption of canonical splicing and aberrant splicing of hundreds of transcripts. However, the functional consequences of this misplicing and resultant genetic vulnerabilities imposed by these events are poorly understood. Through a synthetic-lethal approach we identify that SF3B1 mutant cells are selectively sensitive to PARP inhibitors. This vulnerability is preserved across multiple cell line and patent derived tumour models, independent of SF3B1 hotspot mutation and is manifested both in vitro and in vivo. These data provide the pre-clinical and mechanistic rationale for assessing SF3B1 mutations as a biomarker of single-agent PARP inhibitor response in a new patient population and may extend the clinical utility of these agents beyond BRCA mutated cancers.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: James Wright  

LAB HEAD: Jyoti Choudhary

PROVIDER: PXD019046 | Pride | 2023-04-19

REPOSITORIES: Pride