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Lookup NU author(s): Erhan Aptullahoglu, Mohammed Howladar, Dr Jonathan Wallis, Dr Helen Marr, Professor Julie Irving, Dr Elaine WillmoreORCiD, Professor John LunecORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 by the authors.Background: Chronic lymphocytic leukemia (CLL) treatment has transitioned from traditional chemotherapy to more targeted therapies, but challenges such as resistance and suboptimal responses persist. This study aimed to evaluate HDM201, a second-generation MDM2-p53 binding antagonist, as a novel therapeutic strategy for CLL, with a focus on its effectiveness across different TP53 genetic contexts. Methods: We utilized a panel of B cell leukemia-derived cell lines with varying TP53 statuses, including TP53-knockout (KO) derivatives of the human B cell line Nalm-6, and assessed the impact of HDM201 on primary CLL samples with both TP53 wild-type and mutant backgrounds. Results: Our results revealed that TP53 wild-type and heterozygous TP53-KO Nalm-6 cells were sensitive to HDM201, whereas homozygous TP53-KO cells and B cells with TP53 mutations exhibited significant resistance. Resistance was also noted in primary CLL samples with TP53 mutations. HDM201 effectively stabilized p53 and induced apoptosis in TP53 wild-type cells but had limited efficacy in TP53 mutant cells. Conclusions: These findings indicate that HDM201 holds promise as an additional targeted therapy option for wild-type TP53 CLL. The results underline the importance of TP53 status in predicting treatment efficacy and highlight the potential of HDM201 as a valuable addition to explore in CLL therapy. Future research should focus on identifying additional biomarkers of response and exploring the optimal way to include HDM201 in combination therapies to improve treatment outcomes in CLL.
Author(s): Aptullahoglu E, Howladar M, Wallis JP, Marr H, Marshall S, Irving J, Willmore E, Lunec J
Publication type: Article
Publication status: Published
Journal: Cancers
Year: 2025
Volume: 17
Issue: 2
Online publication date: 16/01/2025
Acceptance date: 09/01/2025
Date deposited: 03/02/2025
ISSN (electronic): 2072-6694
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
URL: https://doi.org/10.3390/cancers17020274
DOI: 10.3390/cancers17020274
Data Access Statement: The data presented in this study and released under a CC-BY 4.0 license are available upon request from the corresponding authors.
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