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Lookup NU author(s): Dr Hayden BellORCiD, Dr Helen Blair, Samantha Jepson Gosling, Dr Martin Galler, Dan AstleyORCiD, Professor Anthony MoormanORCiD, Professor Olaf Heidenreich, Professor Gareth Veal, Dr Frederik van DelftORCiD, Professor John LunecORCiD, Professor Julie Irving
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024.Due to the rarity of TP53 mutations in acute lymphoblastic leukemia (ALL), p53 re-activation by antagonism of the p53-MDM2 interaction represents a potential therapeutic strategy for the majority of ALL. Here, we demonstrate the potent antileukemic activity of the MDM2 antagonist idasanutlin in high-risk and relapsed ex vivo coculture models of TP53 wildtype ALL (n = 40). Insufficient clinical responses to monotherapy MDM2 inhibitors in other cancers prompted us to explore optimal drugs for combination therapy. Utilizing high-throughput combination screening of 1971 FDA-approved and clinically advanced compounds, we identified BCL-xL/BCL-2 inhibitor navitoclax as the most promising idasanutlin combination partner. The idasanutlin-navitoclax combination was synergistically lethal to prognostically-poor, primary-derived and primary patient blasts in ex vivo coculture, and reduced leukemia burden in two very high-risk ALL xenograft models at drug concentrations safely attained in patients; in fact, the navitoclax plasma concentrations were equivalent to those attained in contemporary “low-dose” navitoclax clinical trials. We demonstrate a preferential engagement of cell death over G1 cell cycle arrest, mechanistically implicating MCL-1-binding pro-apoptotic sensitizer NOXA. The proposed combination of two clinical-stage compounds independently under clinical evaluation for ALL is of high clinical relevance and warrants consideration for the treatment of patients with high-risk and relapsed ALL.
Author(s): Bell HL, Blair HJ, Jepson Gosling SJ, Galler M, Astley D, Moorman AV, Heidenreich O, Veal GJ, van Delft FW, Lunec J, Irving JAE
Publication type: Article
Publication status: Published
Journal: Leukemia
Year: 2024
Volume: 38
Pages: 1223-1235
Online publication date: 10/04/2024
Acceptance date: 02/04/2024
Date deposited: 18/04/2024
ISSN (print): 0887-6924
ISSN (electronic): 1476-5551
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41375-024-02241-7
DOI: 10.1038/s41375-024-02241-7
Data Access Statement: Data generated or analyzed during this study are included in this published article and its supplementary information files, or otherwise available from the corresponding author on reasonable request.
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