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Splicing Modulation Results in Aberrant Isoforms and Protein Products of p53 Pathway Genes and the Sensitization of B Cells to Non-Genotoxic MDM2 Inhibition

Lookup NU author(s): Dr Carmela Ciardullo, Dr Jonathan Wallis, Dr Helen Marr, Dr Nicholas Bown, Dr Elaine Willmore, Professor John LunecORCiD

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Abstract

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 TP53^WT cells. It was especially noteworthy that a novel p21^WAF1 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.

Publication metadata

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

PubMed id: 36768733

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