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

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 (PARP...

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Bibliographic Details
Published in:Nature genetics Vol. 55; no. 8; pp. 1311 - 1323
Main Authors: Bland, Philip, Saville, Harry, Wai, Patty T., Curnow, Lucinda, Muirhead, Gareth, Nieminuszczy, Jadwiga, Ravindran, Nivedita, John, Marie Beatrix, Hedayat, Somaieh, Barker, Holly E., 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, Coupland, Sarah E., Broderick, Ronan, Alsafadi, Samar, Houy, Alexandre, Stern, Marc-Henri, Pettit, Stephen, Choudhary, Jyoti S., Haider, Syed, Niedzwiedz, Wojciech, Lord, Christopher J., Natrajan, Rachael
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.08.2023
Nature Publishing Group
Subjects:
13/106
13/51
13/89
631/1647/2217
631/208/212/2019
631/208/212/2166
631/67/1484
631/67/1990/283/1895
64/60
82/58
96/106
96/109
96/95
Adenosine diphosphate
Agriculture
Animal Genetics and Genomics
Anticancer properties
Antitumor activity
Ataxia
Biomarkers
Biomedical and Life Sciences
Biomedicine
BRCA1 Protein - genetics
Cancer
Cancer Research
Cell cycle
Cell Line, Tumor
CHK1 protein
Cyclin-dependent kinase
Cyclin-dependent kinase 2
Cyclin-dependent kinases
DNA biosynthesis
Drug screening
Gene Function
Genes
Genomes
Homologous recombination
Human Genetics
Humans
In vivo methods and tests
Intermediates
Kinases
Leukemia
Medical prognosis
Melanoma
Metastases
Mutation
Mutation hot spots
Neoplasms - drug therapy
Neoplasms - genetics
Phosphoproteins - genetics
Poly(ADP-ribose) polymerase
Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use
Protein expression
Proteins
Replication
Replication origins
Ribose
RNA Splicing Factors - genetics
Transcription Factors - genetics
Tumors
ISSN:1061-4036, 1546-1718, 1546-1718
Online Access:Get full text
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Summary: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. SF3B1 mutations confer sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi). Mechanistically, this is independent of homologous recombination repair and instead relies on a defective replication stress response due to a reduction of the cyclin-dependent kinase 2 interacting protein (CINP). PARPi treatment of SF3B1 mutant ( SF3B1 MUT ) tumors leads to replication stress induced by increased fork origin firing and culminates in cell cycle stalling.
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ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/s41588-023-01460-5