SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.
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Authors
Bland, P
Saville, H
Wai, PT
Curnow, L
Muirhead, G
Nieminuszczy, J
Ravindran, N
John, MB
Hedayat, S
Barker, HE
Wright, J
Yu, L
Mavrommati, I
Read, A
Peck, B
Allen, M
Gazinska, P
Pemberton, HN
Gulati, A
Nash, S
Noor, F
Guppy, N
Roxanis, I
Pratt, G
Oldreive, C
Stankovic, T
Barlow, S
Kalirai, H
Coupland, SE
Broderick, R
Alsafadi, S
Houy, A
Stern, M-H
Pettit, S
Choudhary, JS
Haider, S
Niedzwiedz, W
Lord, CJ
Natrajan, R
Saville, H
Wai, PT
Curnow, L
Muirhead, G
Nieminuszczy, J
Ravindran, N
John, MB
Hedayat, S
Barker, HE
Wright, J
Yu, L
Mavrommati, I
Read, A
Peck, B
Allen, M
Gazinska, P
Pemberton, HN
Gulati, A
Nash, S
Noor, F
Guppy, N
Roxanis, I
Pratt, G
Oldreive, C
Stankovic, T
Barlow, S
Kalirai, H
Coupland, SE
Broderick, R
Alsafadi, S
Houy, A
Stern, M-H
Pettit, S
Choudhary, JS
Haider, S
Niedzwiedz, W
Lord, CJ
Natrajan, R
Document Type
Journal Article
Date
2023-08-01
Date Accepted
2023-06-26
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 (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUT 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 SF3B1MUT 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.
Citation
Nature Genetics, 2023, 55 (8), pp. 1311 - 1323
Source Title
Nature Genetics
Publisher
NATURE PORTFOLIO
ISSN
1061-4036
eISSN
1546-1718
1546-1718
1546-1718
Collections
Research Team
Functional Proteomics
Prote & Metabolomics Fac
BCR Bioinformatics Group
Cancer and Genome Instab
Gene Function
Functional Genomics
Prote & Metabolomics Fac
BCR Bioinformatics Group
Cancer and Genome Instab
Gene Function
Functional Genomics