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Peer-reviewedCC BYActa neuropathologica communications

Cytotoxic activity of selinexor in BRAFV600E-driven pediatric low-grade glioma 3D cultures.

  • Constantia Zeiser1,2,3,4
  • Marta Emperador1,2,3,5
  • Sonja Herter1,2,3,5
  • Lisa Sigaud1,2,3,5
  • Alexandra Stroh-Dege1,2,3
  • Anna Loboda1,2,3,5
  • Anna Kolodziejczak1,2,3
  • Simon Zeuner1,2,3,6
  • Lea Joy Digel1,2,3
  • Karen Frese7
  • Bruno Chilian8
  • Micaela Freitas9
10 more authors
  • Jens M Kelm9
  • Ingrid Ǿra10,11
  • Daniel Vogl12
  • Martin Ulrich Schuhmann13
  • Heike Peterziel1,2,3
  • Romain Sigaud1,2,3,14
  • Florian Selt1,2,3,6
  • Till Milde1,2,3,14
  • Olaf Witt1,2,3,6
  • Ina Oehme15,16,17,18
18 affiliations
  1. 1Hopp Children's Cancer Center Heidelberg (KiTZ), 69120, Heidelberg, Germany.
  2. 2Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
  3. 3National Center for Tumor Diseases (NCT), NCT Heidelberg, Heidelberg University Hospital, 69120, Heidelberg, Germany.
  4. 4Faculty of Medicine, Heidelberg University, 69120, Heidelberg, Germany.
  5. 5Faculty of Biosciences, Heidelberg University, 69120, Heidelberg, Germany.
  6. 6Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, 69120, Heidelberg, Germany.
  7. 7Department of Medicine III, Heidelberg University, German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, 69120, Heidelberg, Germany.
  8. 8TRI Thinking Research Instruments GmbH, Große Freiheit 77, 22767, Hamburg, Germany.
  9. 9Precomb Therapeutics AG, Hombrechtikon, Switzerland.
  10. 10Lund University, Lund, Sweden.
  11. 11Karolinska University Hospital, Stockholm, Sweden.
  12. 12Department of Neurosurgery, Section of Pediatric Neurosurgery, University Hospital Tuebingen, Hoppe-Seyler-Str. 3, Baden-Württemberg, 72076, Tuebingen, Germany.
  13. 13Department of Neurosurgery, Centre of Neurofibromatosis and Schwannomatosis, Centre for Rare Diseases, Division of Pediatric Neurosurgery, University Hospital Tübingen, Tübingen, Germany.
  14. 14Department of Pediatrics and Adolescent Medicine, University Hospital Jena, Friedrich Schiller University Jena and Comprehensive Cancer Center Central Germany (CCCG), Jena, Germany.
  15. 15Hopp Children's Cancer Center Heidelberg (KiTZ), 69120, Heidelberg, Germany. [email protected].
  16. 16Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120, Heidelberg, Germany. [email protected].
  17. 17National Center for Tumor Diseases (NCT), NCT Heidelberg, Heidelberg University Hospital, 69120, Heidelberg, Germany. [email protected].
  18. 18Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, 69120, Heidelberg, Germany. [email protected].
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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.

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Cite

BibTeXRIS
BibTeX
@article{zeiser2026cytotoxic,
  title = {{Cytotoxic activity of selinexor in BRAFV600E-driven pediatric low-grade glioma 3D cultures.}},
  author = {Constantia Zeiser and Marta Emperador and Sonja Herter and Lisa Sigaud and Alexandra Stroh-Dege and Anna Loboda and Anna Kolodziejczak and Simon Zeuner and Lea Joy Digel and Karen Frese and Bruno Chilian and Micaela Freitas and Jens M Kelm and Ingrid Ǿra and Daniel Vogl and Martin Ulrich Schuhmann and Heike Peterziel and Romain Sigaud and Florian Selt and Till Milde and Olaf Witt and Ina Oehme},
  journal = {Acta neuropathologica communications},
  year = {2026},
  month = oct,
  doi = {10.1186/s40478-026-02461-1},
  url = {https://europepmc.org/article/MED/42919430},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Cytotoxic activity of selinexor in BRAFV600E-driven pediatric low-grade glioma 3D cultures.
AU  - Constantia Zeiser
AU  - Marta Emperador
AU  - Sonja Herter
AU  - Lisa Sigaud
AU  - Alexandra Stroh-Dege
AU  - Anna Loboda
AU  - Anna Kolodziejczak
AU  - Simon Zeuner
AU  - Lea Joy Digel
AU  - Karen Frese
AU  - Bruno Chilian
AU  - Micaela Freitas
AU  - Jens M Kelm
AU  - Ingrid Ǿra
AU  - Daniel Vogl
AU  - Martin Ulrich Schuhmann
AU  - Heike Peterziel
AU  - Romain Sigaud
AU  - Florian Selt
AU  - Till Milde
AU  - Olaf Witt
AU  - Ina Oehme
PY  - 2026
DA  - 2026/10/22
JO  - Acta neuropathologica communications
DO  - 10.1186/s40478-026-02461-1
UR  - https://europepmc.org/article/MED/42919430
AB  - 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.
SN  - 2051-5960
ER  -