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

Collapse authors list.
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) , Wright, James, Yu, Lu, Mavrommati, Ioanna, Read, Abigail, Peck, Barrie, Allen, Mark, Gazinska, Patrycja, Pemberton, Helen N, Gulati, Aditi, Nash, Sarah, Noor, Farzana, Guppy, Naomi, Roxanis, Ioannis, Pratt, Guy, Oldreive, Ceri, Stankovic, Tatjana, Barlow, Samantha, Kalirai, Helen ORCID: 0000-0002-4440-2576, Coupland, Sarah E ORCID: 0000-0002-1464-2069, Broderick, Ronan, Alsafadi, Samar, Houy, Alexandre, Stern, Marc-Henri, Pettit, Stephen, Choudhary, Jyoti S, Haider, Syed, Niedzwiedz, Wojciech, Lord, Christopher J and Natrajan, Rachael (2023) SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response. NATURE GENETICS, 55 (8). 1311-+.

Access the full-text of this item by clicking on the Open Access link.

Abstract

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^MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1^MUT 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 G₂/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^MUT 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:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3173155