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doi:10.22028/D291-45432
Titel: | An in vitro pharmacogenomic approach reveals subtype-specific therapeutic vulnerabilities in atypical teratoid/rhabdoid tumors (AT/RT) |
VerfasserIn: | Pauck, David Picard, Daniel Maue, Mara Taban, Kübra Marquardt, Viktoria Blümel, Lena Bartl, Jasmin Qin, Nan Kubon, Nadezhda Schöndorf, Dominik Meyer, Frauke-Dorothee Theruvath, Johanna Mitra, Siddhartha Hasselblatt, Martin Frühwald, Michael C. Reifenberger, Guido Remke, Marc |
Sprache: | Englisch |
Titel: | Pharmacological Research |
Bandnummer: | 213 |
Verlag/Plattform: | Elsevier |
Erscheinungsjahr: | 2025 |
Freie Schlagwörter: | Atypical teratoid/rhabdoid tumor DNA methylation profiling High-throughput drug screening RNA sequencing Targeted therapy |
DDC-Sachgruppe: | 610 Medizin, Gesundheit |
Dokumenttyp: | Journalartikel / Zeitschriftenartikel |
Abstract: | Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal brain tumor driven by genetic alterations inactivating the SMARCB1 or, less commonly, the SMARCA4 gene. Large-scale molecular profiling studies have identified distinct molecular subtypes termed AT/RT-TYR, -SHH and -MYC. Despite the increasing knowledge of AT/RT biology, curative treatment options are still lacking for certain risk groups and outcomes of these patients remain poor. We performed an in vitro high-throughput drug screen of 768 small molecule drugs covering conventional chemotherapeutic agents and late-stage developmental drugs in 13 AT/RT cell lines and determined intra- and inter-entity differential responses to unravel specific vulnerabilities. Our data demonstrated in vitro preferential activity of mitogen-activated protein kinase kinase (MEK) and mouse double minute 2 homolog (MDM2) inhibitors in AT/RT cell lines compared to other high-grade brain tumor cell lines including medulloblastoma and malignant glioma models. Moreover, we were able to link distinct drug response patterns to AT/RT molecular subtypes through integration of drug response data with large-scale DNA methylation and RNASeq-based expression profiles. Subtype-dependent drug response profiles demonstrated sensitivity of AT/RT-SHH cell lines to B-cell lymphoma 2 (BCL2) and heat shock protein 90 (HSP90) inhibitors, and increased activity of microtubule inhibitors, kinesin spindle protein (KSP) inhibitors, and the eukaryotic translation initiation factor 4E (eIF4E) inhibitor briciclib in a subset of AT/RT-MYC cell lines. In summary, our in vitro pharmacogenomic approach revealed preclinical evidence of tumor type- and subtype-specific therapeutic vulnerabilities in AT/RT cell lines that may inform future in vivo and clinical evaluations of novel pharmacological strategies. |
DOI der Erstveröffentlichung: | 10.1016/j.phrs.2025.107660 |
URL der Erstveröffentlichung: | https://doi.org/10.1016/j.phrs.2025.107660 |
Link zu diesem Datensatz: | urn:nbn:de:bsz:291--ds-454323 hdl:20.500.11880/40035 http://dx.doi.org/10.22028/D291-45432 |
ISSN: | 1096-1186 1043-6618 |
Datum des Eintrags: | 26-Mai-2025 |
Bezeichnung des in Beziehung stehenden Objekts: | Supporting information |
In Beziehung stehendes Objekt: | https://ars.els-cdn.com/content/image/1-s2.0-S1043661825000854-mmc1.docx |
Fakultät: | M - Medizinische Fakultät |
Fachrichtung: | M - Pädiatrie |
Professur: | M - Prof. Dr. Michael Zemlin |
Sammlung: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
Dateien zu diesem Datensatz:
Datei | Beschreibung | Größe | Format | |
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1-s2.0-S1043661825000854-main.pdf | 6,6 MB | Adobe PDF | Öffnen/Anzeigen |
Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons