SF3B1 hotspot mutations confer a targetable replication stress response defect (ChIP-Seq)
Cancer-associated mutations in the RNA splicing factor SF3B1 commonly occur in leukemias, as well as in a variety of solid cancers leading to global disruption of canonical splicing and subsequent dependence on wild-type splicing. The functional consequences of the mis-splicing events are poorly understood and precision medicine approaches that exploit these characteristics are not clinically available. Through synthetic-lethal drug screens we identify that SF3B1 mutant cells are selectively sensitive to PARP1/2 inhibitors, mediated through PARP1 trapping. SF3B1 mutant cells displayed increased transcriptional stress and a defective response to PARPi induced replication stress. Mechanistically this occurs via downregulation of the novel CDK2 interacting protein CINP in SF3B1 mutant cells and leads to a lack of P-Chk1 (S317) induction when the replication fork is accelerated under PARPi treatment. The resultant replication stress leads to DNA damage and cell cycle stalling at the G2/M checkpoint, which can be rescued through CINP overexpression, or further targeted by ATM inhibition in combination with PARPi treatment. This vulnerability is preserved across multiple cell line and patent derived tumour models, independent of SF3B1 hotspot mutation. In vivo, PARP inhibitors produced profound antitumor effects in multiple SF3B1 mutant cancer models and eliminated distant metastases. These data provide the pre-clinical and mechanistic rationale for the clinical efficacy of licensed PARP inhibitor drugs in a new biomarker driven HR proficient patient population irrespective of tumour site and hence may extend the clinical utility of these agents beyond BRCA1/2 mutated cancers.