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

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, MH; Pettit, S; Choudhary, JS; Haider, S; Niedzwiedz, W; Lord, CJ; Natrajan, R

Author(s): 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, MH; Pettit, S; Choudhary, JS; Haider, S; Niedzwiedz, W; Lord, CJ; Natrajan, R;
Details: Publication Year 2023-07-31,Volume 55,Issue #8,Page 1311-1323
Journal Title: Nature Genetics
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 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.
Publisher: NPG
Keywords: Humans; *Poly(ADP-ribose) Polymerase Inhibitors/pharmacology/therapeutic use; Mutation; Transcription Factors/genetics; *Neoplasms/drug therapy/genetics; BRCA1 Protein/genetics; Cell Line, Tumor; RNA Splicing Factors/genetics; Phosphoproteins/genetics
Research Division(s): Cancer Biology And Stem Cells
PubMed ID: 37524790
Publisher's Version: https://doi.org/10.1038/s41588-023-01460-5
Open Access at Publisher's Site: https://doi.org/10.1038/s41588-023-01460-5
Terms of Use/Rights Notice: Refer to copyright notice on published article.
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Creation Date: 2023-08-04 12:44:13

Last Modified: 2023-11-20 03:24:04