SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response

Bland, Philip, Saville, Harry, Wai, Patty T, Curnow, Lucinda, Muirhead, Gareth, Nieminuszczy, Jadwiga, Ravindran, Nivedita, John, Marie Beatrix, Hedayat, Somaieh, Barker, Holly E
et al (show 29 more authors) (2023) SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response. NATURE GENETICS, 55 (8). 1311-+.

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SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant (SF3B1<sup>MUT</sup>) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1<sup>MUT</sup> cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G<sub>2</sub>/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1<sup>MUT</sup> cancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population.

Item Type: Article
Uncontrolled Keywords: Cell Line, Tumor, Humans, Neoplasms, BRCA1 Protein, Phosphoproteins, Transcription Factors, Mutation, Poly(ADP-ribose) Polymerase Inhibitors, RNA Splicing Factors
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 28 Sep 2023 10:16
Last Modified: 28 Sep 2023 10:17
DOI: 10.1038/s41588-023-01460-5
Open Access URL: https://doi.org/10.1038/s41588-023-01460-5
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3173155