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

Abstract

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.