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

2023; Nature Portfolio; Volume: 55; Issue: 8 Linguagem: Inglês

10.1038/s41588-023-01460-5

1546-1718

Philip Bland, Harry Saville, Patty T. Wai, Lucinda Curnow, Gareth Muirhead, Jadwiga Nieminuszczy, Nivedita Ravindran, Marie John, Somaieh Hedayat, Holly E. Barker, James C. Wright, Lu Yu, Ioanna Mavrommati, Abigail Read, Barrie Peck, Mark Allen, Patrycja Gazińska, Helen N. Pemberton, Aditi Gulati, Sarah H. Nash, Farzana Noor, Naomi Guppy, Ioannis Roxanis, Guy Pratt, Ceri Oldreive, Tatjana Stanković, Samantha L Barlow, Helen Kalirai, Sarah E. Coupland, Ronan Broderick, Samar Alsafadi, Alexandre Houy, Marc‐Henri Stern, Stephen Pettit, Jyoti S. Choudhary, Syed Haider, Wojciech Niedźwiedź, Christopher J. Lord, Rachael Natrajan,

CRISPR and Genetic Engineering

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 G 2 /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.