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

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

doi:10.1038/s41588-023-01460-5

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

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

^*Corresponding author for this work

Cancer and Genomic Sciences

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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 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 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.

Original language	English
Pages (from-to)	1311-1323
Number of pages	13
Journal	Nature Genetics
Volume	55
Issue number	8
Early online date	31 Jul 2023
DOIs	https://doi.org/10.1038/s41588-023-01460-5
Publication status	Published - Aug 2023

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Bland, P., Saville, H., Wai, P. T., Curnow, L., Muirhead, G., Nieminuszczy, J., Ravindran, N., John, M. B., Hedayat, S., Barker, H. E., Wright, J., Yu, L., Mavrommati, I., Read, A., Peck, B., Allen, M., Gazinska, P., Pemberton, H. N., Gulati, A., ... Natrajan, R. (2023). SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response. Nature Genetics, 55(8), 1311-1323. https://doi.org/10.1038/s41588-023-01460-5

@article{4b6a7f06a6084f50be8b0ed1e97ae1e1,

title = "SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response",

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.",

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

year = "2023",

month = aug,

doi = "10.1038/s41588-023-01460-5",

language = "English",

volume = "55",

pages = "1311--1323",

journal = "Nature Genetics",

issn = "1061-4036",

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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 2023, 'SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response', Nature Genetics, vol. 55, no. 8, pp. 1311-1323. https://doi.org/10.1038/s41588-023-01460-5

TY - JOUR

T1 - SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response

AU - Bland, Philip

AU - Saville, Harry

AU - Wai, Patty T.

AU - Curnow, Lucinda

AU - Muirhead, Gareth

AU - Nieminuszczy, Jadwiga

AU - Ravindran, Nivedita

AU - John, Marie Beatrix

AU - Hedayat, Somaieh

AU - Barker, Holly E.

AU - Wright, James

AU - Yu, Lu

AU - Mavrommati, Ioanna

AU - Read, Abigail

AU - Peck, Barrie

AU - Allen, Mark

AU - Gazinska, Patrycja

AU - Pemberton, Helen N.

AU - Gulati, Aditi

AU - Nash, Sarah

AU - Noor, Farzana

AU - Guppy, Naomi

AU - Roxanis, Ioannis

AU - Pratt, Guy

AU - Oldreive, Ceri

AU - Stankovic, Tatjana

AU - Barlow, Samantha

AU - Kalirai, Helen

AU - Coupland, Sarah E.

AU - Broderick, Ronan

AU - Alsafadi, Samar

AU - Houy, Alexandre

AU - Stern, Marc-Henri

AU - Pettit, Stephen

AU - Choudhary, Jyoti S.

AU - Haider, Syed

AU - Niedzwiedz, Wojciech

AU - Lord, Christopher J.

AU - Natrajan, Rachael

PY - 2023/8

Y1 - 2023/8

N2 - 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.

AB - 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.

U2 - 10.1038/s41588-023-01460-5

DO - 10.1038/s41588-023-01460-5

M3 - Article

SN - 1061-4036

VL - 55

SP - 1311

EP - 1323

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

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

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