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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 BRAF\n                    <jats:sup>V600E<\/jats:sup>\n                    -mutant BT40 3D multicellular aggregates and subsequently evaluated the prioritized XPO1-targeting strategy in BRAF\n                    <jats:sup>V600E<\/jats:sup>\n                    -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 BRAF\n                    <jats:sup>V600E<\/jats:sup>\n                    -induced senescence models revealed upregulation of MAPK, TGF\u03b2, 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\u00a0h 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 BRAF\n                    <jats:sup>V600E<\/jats:sup>\n                    -driven pLGG that warrants further preclinical evaluation.\n                  <\/jats:p>","DOI":"10.1186\/s40478-026-02461-1","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T07:15:35Z","timestamp":1792653335000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cytotoxic activity of selinexor in BRAFV600E-driven pediatric low-grade glioma 3D cultures"],"prefix":"10.1186","volume":"14","author":[{"given":"Constantia","family":"Zeiser","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Emperador","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Herter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Sigaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Stroh-Dege","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Loboda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Kolodziejczak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Zeuner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea Joy","family":"Digel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Frese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Chilian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micaela","family":"Freitas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens M.","family":"Kelm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"\u01fera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Vogl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin Ulrich","family":"Schuhmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Peterziel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romain","family":"Sigaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Selt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Till","family":"Milde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Witt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0827-2356","authenticated-orcid":false,"given":"Ina","family":"Oehme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,22]]},"reference":[{"key":"2461_CR1","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1093\/neuonc\/noq178","volume":"13","author":"GT Armstrong","year":"2011","unstructured":"Armstrong GT, Conklin HM, Huang S, Srivastava D, Sanford R, Ellison DW, Merchant TE, Hudson MM, Hoehn ME, Robison LLet al et al (2011) Survival and long-term health and cognitive outcomes after low-grade glioma. 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Genomics Proteom Bioinf 20:587\u2013596. https:\/\/doi.org\/10.1016\/j.gpb.2022.01.004","journal-title":"Genomics Proteom Bioinf"}],"container-title":["Acta Neuropathologica Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40478-026-02461-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-026-02461-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-026-02461-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T20:02:25Z","timestamp":1792699345000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40478-026-02461-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,22]]},"references-count":81,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["2461"],"URL":"https:\/\/doi.org\/10.1186\/s40478-026-02461-1","relation":{},"ISSN":["2051-5960"],"issn-type":[{"value":"2051-5960","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,22]]},"assertion":[{"value":"6 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 October 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 October 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. All patients, their legally acceptable representatives, or both (if possible) provided written informed consent. Approval for the study protocol (and any modi\ufb01cations thereof) was obtained from independent ethics committees and the institutional review board at each participating center. The INFORM registry was registered with the German Clinical Trial Register, number DRKS00007623. The LOGGIC Core BioClinical Data Bank is a centralized biobank and clinical data repository established within the LOGGIC consortium (Low-Grade Glioma in Children), a Germany-wide research and clinical network. Fresh tumor tissue was collected via the LOGGIC Core BioClinical Data Bank following approval by the responsible ethics committees (S-064\/2019) and after written informed consent from patients and\/or their legal guardians. The use of patient-derived material for ex vivo functional analyses complied with institutional, national, and international ethical standards and the Declaration of Helsinki.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Care and breeding of zebrafish (Danio rerio) were under institutional approval of the Regierungspr\u00e4sidium Karlsruhe (35-9185.64), which conform to the Guide for the Care and Use of Laboratory Animals published by The US National Institute of Health (NIH Publication No. 85\u2009\u2212\u200923, revised 1996). All applicable national and institutional guidelines for the care and use of zebrafish were followed. All procedures involving animals were performed in accordance with the ethical standards of the Medical Faculty University Hospital Heidelberg.","order":3,"name":"Ethics","label":"Institutional review board statement","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"OW participated in advisory boards of Novartis, BMS, Janssen and receives research grants from BVD, Day One Therapeutics. IO receives research grants from PreComb, BVD and Day One Therapeutics. BC is employed as CSO at TRI Thinking Research Instruments GmbHT.M. has received research grants from Biomed Valley Discoveries, Inc. and Day One Biopharmaceuticals, and participated in advisory boards of Ipsen Pharma.","order":4,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"220"}}