Navitoclax acts synergistically with irradiation to induce apoptosis in preclinical models of H3K27M-altered diffuse midline glioma

Diffuse midline gliomas (DMGs) with histone H3K27M mutations represent a devastating paediatric brain cancer characterised by abysmal prognosis and limited treatment options. The only approved treatment is radiotherapy (RT), but most of the tumours relapse with fatal consequences. The effects of RT remain unknown because patients are not biopsied during treatment. Here, we sought to investigate whether irradiation leads to senescence induction in DMG and explore the efficacy of senolytics. We show that ionising radiation induces senescence in various H3K27M-altered DMG cell lines. Senescence induction is demonstrated by immunocytochemistry, RNA-sequencing and analysis of SASP factors by ELISA. Through testing several senolytic compounds, we identify that Bcl2 family inhibitors (e.g., Navitoclax) act as potent senolytics, driving senescent DMG cells into apoptosis, primarily via Bcl-xL inhibition. Reinforcing these findings, proteolysis-targeting chimeras (PROTACs) targeting Bcl-xL and galacto-conjugated Navitoclax (Nav-Gal) also exhibit strong senolytic activity against senescent DMG cancer cells. Finally, we show that a combination of irradiation with Navitoclax enhances cancer cell apoptosis in an orthotopic xenograft DMG model. Together, the data demonstrate that ionising irradiation leads to senescence induction in H3K27M-altered human DMG cell lines, making them particularly sensitive to apoptosis through Bcl-xL inhibition.

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Publication Details

Journal
Scientific Reports
Published
2025-12-22
DOI
https://doi.org/10.1038/s41598-025-32676-6
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
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article

Navitoclax acts synergistically with irradiation to induce apoptosis in preclinical models of H3K27M-altered diffuse midline glioma

Darren Hargrave, John Apps, Jesús Gil, Scott Haston et al.
Scientific Reports
Protein Degradation and Inhibitors
article

Navitoclax acts synergistically with irradiation to induce apoptosis in preclinical models of H3K27M-altered diffuse midline glioma

Darren Hargrave, John Apps, Jesús Gil, Scott Haston, Paula Alexandre, Daohong Zhou, James F. E. Grey, Grace Cooksley, Ielyaas Cloete, M Lythgoe, Diana Martins Carvalho, J. P. Martinez-Barbera, David Michod, Ashley Vardon, Ángel M. Carcaboso, Rebecca Carter, Ying Hong, C. Michael Jones, O. R. Williams, G Y Zheng, Hiba Hamdi, Daniel Gharai, Laura Kate Donovan, Jamie Adam Dean, Jessica Katherine Rowena Boult, Romain Guiho, Ramón Martínez-Máñez
article en

Abstract

Diffuse midline gliomas (DMGs) with histone H3K27M mutations represent a devastating paediatric brain cancer characterised by abysmal prognosis and limited treatment options. The only approved treatment is radiotherapy (RT), but most of the tumours relapse with fatal consequences. The effects of RT remain unknown because patients are not biopsied during treatment. Here, we sought to investigate whether irradiation leads to senescence induction in DMG and explore the efficacy of senolytics. We show that ionising radiation induces senescence in various H3K27M-altered DMG cell lines. Senescence induction is demonstrated by immunocytochemistry, RNA-sequencing and analysis of SASP factors by ELISA. Through testing several senolytic compounds, we identify that Bcl2 family inhibitors (e.g., Navitoclax) act as potent senolytics, driving senescent DMG cells into apoptosis, primarily via Bcl-xL inhibition. Reinforcing these findings, proteolysis-targeting chimeras (PROTACs) targeting Bcl-xL and galacto-conjugated Navitoclax (Nav-Gal) also exhibit strong senolytic activity against senescent DMG cancer cells. Finally, we show that a combination of irradiation with Navitoclax enhances cancer cell apoptosis in an orthotopic xenograft DMG model. Together, the data demonstrate that ionising irradiation leads to senescence induction in H3K27M-altered human DMG cell lines, making them particularly sensitive to apoptosis through Bcl-xL inhibition.

Scientific ReportsVol. 15(1)
Hospital Sant Joan de Déu Barcelona (ES), Institute of Cancer Research (GB), Inserm (FR), Universitat de València (ES), The University of Texas at San Antonio Health Science Center (US), University of Florida Health (US), Cancer Research UK (GB), Instituto de Salud Carlos III (ES), Brain Tumour Charity (GB), Brain Tumour Research (GB), Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (ES), Living Streets (GB), CRUK Lung Cancer Centre of Excellence (GB), MRC London Institute of Medical Sciences (GB), Living Systems (United States) (US), UF Health Cancer Center, University College London (GB), Imperial College London (GB), Universitat Politècnica de València (ES), University of Birmingham (GB), Nantes Université (FR)
Cancer Research UK, University College London, Great Ormond Street Hospital for Children, Brain Tumour Research, National Institutes of Health, Medical Research Council
Good health and well-being
Openalex Percentile: Top 37%
Protein Degradation and Inhibitors
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