SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.
Date
2023-08-01ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Humans
Poly(ADP-ribose) Polymerase Inhibitors
Mutation
Transcription Factors
Neoplasms
BRCA1 Protein
Cell Line, Tumor
RNA Splicing Factors
Phosphoproteins
Research team
Functional Proteomics
Prote & Metabolomics Fac
BCR Bioinformatics Group
Cancer and Genome Instab
Gene Function
Functional Genomics
Language
eng
Date accepted
2023-06-26
License start date
2023-08-01
Citation
Nature Genetics, 2023, 55 (8), pp. 1311 - 1323
Publisher
NATURE PORTFOLIO