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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Vydáno v:	Nature genetics Ročník 55; číslo 8; s. 1311 - 1323
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	New York Nature Publishing Group US 01.08.2023 Nature Publishing Group
Témata:	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
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-023-01460-5