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| Home > Publications database > Cytotoxic activity of selinexor in BRAFV600E-driven pediatric low-grade glioma 3D cultures. |
| Home > Publications database > Cytotoxic activity of selinexor in BRAFV600E-driven pediatric low-grade glioma 3D cultures. |
| Journal Article | DKFZ-2026-02622 |
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2026
Biomed Central
London
Abstract: Pediatric low-grade gliomas (pLGGs) are the most common primary brain tumors in children and frequently harbor activating RAS/MAPK pathway alterations, including BRAFV600E. Although MEK inhibitors (MEKi) show clinical activity, responses are often incomplete and tumors commonly regrow after treatment discontinuation, highlighting the need for therapies that induce sustained regression. To systematically identify cytotoxic treatments, we initially screened 87 clinically relevant drugs in BRAFV600E-mutant BT40 3D multicellular aggregates and subsequently evaluated the prioritized XPO1-targeting strategy in BRAFV600E-mutant DKFZ-BT314 spheroids in proliferative (ON) and senescent (OFF) states and in fresh pLGG tissue cultures. High-content imaging with machine-learning-based analysis identified XPO1 inhibition as a vulnerability across models. The FDA-approved selective XPO1 inhibitor selinexor was active alone and in combination with MEKi. MEK-XPO1 co-inhibition reduced viable 3D culture area by more than 30% and suppressed regrowth for at least 10 d, even after medium change. DRAQ7 positivity and caspase-3/7 activation demonstrated cell death in the 3D cultures, while complementary 2D analyses showed PARP cleavage, nuclear fragmentation, and caspase activation. Transcriptomic analyses of pleomorphic xanthoastrocytoma patient samples and BRAFV600E-induced senescence models revealed upregulation of MAPK, TGFβ, TP53, and FOXO pathway genes and anti-apoptotic BCL2 family members, including MCL-1. XPO1 inhibition reduced MCL-1 protein levels, consistent with disruption of anti-apoptotic signaling. Ex vivo drug sensitivity profiling of fresh tumor tissue from 20 patients from the LOGGIC Core BioClinical Data Bank demonstrated sensitivity to XPO1 inhibition at clinically achievable concentrations. In an exploratory BT40 zebrafish embryo xenograft experiment, 48 h of combination treatment numerically attenuated tumor growth compared with solvent treatment, although the difference was not statistically significant. Overall, our findings support XPO1 inhibition, alone or combined with MEK inhibition, as a candidate therapeutic strategy for BRAFV600E-driven pLGG that warrants further preclinical evaluation.
Keyword(s): Humans (MeSH) ; Triazoles: pharmacology (MeSH) ; Glioma: genetics (MeSH) ; Glioma: drug therapy (MeSH) ; Glioma: pathology (MeSH) ; Hydrazines: pharmacology (MeSH) ; Brain Neoplasms: genetics (MeSH) ; Brain Neoplasms: drug therapy (MeSH) ; Brain Neoplasms: pathology (MeSH) ; Proto-Oncogene Proteins B-raf: genetics (MeSH) ; Exportin 1 Protein (MeSH) ; Karyopherins: antagonists & inhibitors (MeSH) ; Antineoplastic Agents: pharmacology (MeSH) ; Child (MeSH) ; Receptors, Cytoplasmic and Nuclear: antagonists & inhibitors (MeSH) ; Cell Line, Tumor (MeSH) ; Mutation (MeSH) ; Animals (MeSH) ; 3D culture ; Brain tumor ; Drug repurposing ; Ex vivo drug profiling ; Exportin-1 (XPO1) ; Functional precision oncology ; MAPK pathway ; Pediatric low-grade glioma ; Synergy screening ; Targeted therapy ; Triazoles ; Hydrazines ; selinexor ; Proto-Oncogene Proteins B-raf ; Exportin 1 Protein ; Karyopherins ; BRAF protein, human ; Antineoplastic Agents ; Receptors, Cytoplasmic and Nuclear
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