Across multiple cancer types, hotspot mutations in SF3B1 confer selective sensitivity to multiple clinically available PARP inhibitors. This sensitivity is due to reduced levels of CINP specifically in SF3B1-mutant cells, which leads to a loss of the canonical replication stress response after challenge with PARP inhibitors.
This is a preview of subscription content, log in via an institution to check access.
References
Yoshimi, D. & Abdel-Wahab, O. Molecular pathways: understanding and targeting mutant spliceosomal proteins. Clin. Cancer Res. 23, 336–341 (2017). This review discusses the role of mutations in spliceosomal component proteins.
Alsafadi, S. et al. Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage. Nat. Commun. 7, 10615 (2016). This is one of the first reports describing the mis-splicing events in SF3B1MUT cancers and the mechanism behind this.
Liu, Z. et al. Mutations in the RNA splicing factor SF3B1 promote tumorigenesis through MYC stabilization. Cancer Discov. 10, 806–821 (2020). This paper reports that SF3B1MUT cancers show hyperactivation of the proto-oncoprotein MYC that promotes tumor growth.
Inoue, D. et al. Spliceosomal disruption of the non-canonical BAF complex in cancer. Nature 574, 432–436 (2019). This paper shows that mis-splicing of the chromatin-remodeling protein BRD9 drives tumorigenesis in SF3B1MUT cancers and can be rescued through morpholino delivery.
Pratt, G. et al. A multi-centre phase I trial of the PARP inhibitor olaparib in patients with relapsed chronic lymphocytic leukaemia, T-prolymphocytic leukaemia or mantle cell lymphoma. Br. J. Haematol. 182, 429–433 (2018). This paper reports a phase 1 clinical trial of olaparib in treatment-refractory leukemias; this is the only clinical trial of a PARP inhibitor in patients with known SF3B1 mutations.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This is a summary of: Bland, P. et al. SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response. Nat. Genet. https://doi.org/10.1038/s41588-023-01460-5 (2023).
Rights and permissions
About this article
Cite this article
SF3B1-mutant cells succumb to replication stress under PARP inhibition. Nat Genet 55, 1265–1266 (2023). https://doi.org/10.1038/s41588-023-01461-4
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41588-023-01461-4
- Springer Nature America, Inc.