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Lookup NU author(s): Dr Carmela Ciardullo, Dr Jonathan Wallis, Dr Helen Marr, Dr Nicholas Bown, Dr Elaine Willmore, Professor John LunecORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Several molecular subtypes of cancer are highly dependent on splicing for cell survival. There is a general interest in the therapeutic targeting of splicing by small molecules. E7107, a first-in-class spliceosome inhibitor, showed strong growth inhibitory activities against a large variety of human cancer xenografts. Chronic lymphocytic leukaemia (CLL) is a clinically heterogeneous hematologic malignancy, with approximately 90% of cases being TP53 wild-type at diagnosis. An increasing number of studies are evaluating alternative targeted agents in CLL, including MDM2–p53 binding antagonists. In this study, we report the effect of splicing modulation on key proteins in the p53 signalling pathway, an important cell death pathway in B cells. Splicing modulation by E7107 treatment reduced full-length MDM2 production due to exon skipping, generating a consequent reciprocal p53 increase in TP53WT cells. It was especially noteworthy that a novel p21WAF1 isoform with compromised cyclin-dependent kinase inhibitory activity was produced due to intron retention. E7107 synergized with the MDM2 inhibitor RG7388, via dual MDM2 inhibition; by E7107 at the transcript level and by RG7388 at the protein level, producing greater p53 stabilisation and apoptosis. This study provides evidence for a synergistic MDM2 and spliceosome inhibitor combination as a novel approach to treat CLL and potentially other haematological malignancies.
Author(s): Aptullahoglu A, Ciardullo C, Wallis JP, Marr H, Marshall S, Bown N, Willmore E, Lunec J
Publication type: Article
Publication status: Published
Journal: International Journal of Molecular Sciences
Year: 2023
Volume: 24
Issue: 3
Online publication date: 26/01/2023
Acceptance date: 24/01/2023
Date deposited: 02/02/2024
ISSN (electronic): 1422-0067
Publisher: MDPI
URL: https://doi.org/10.3390/ijms24032410
DOI: 10.3390/ijms24032410
Data Access Statement: Not applicable.
PubMed id: 36768733
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