%0 Journal Article
%A Pauck, David
%A Picard, Daniel Joseph
%A Maue, Mara
%A Taban, Kübra
%A Marquardt, Viktoria
%A Blümel, Lena
%A Bartl, Jasmin
%A Qin, Nan
%A Kubon, Nadezhda
%A Schöndorf, Dominik
%A Meyer, Frauke-Dorothee
%A Theruvath, Johanna
%A Mitra, Siddhartha
%A Hasselblatt, Martin
%A Frühwald, Michael C
%A Reifenberger, Guido
%A Remke, Marc
%T An in vitro pharmacogenomic approach reveals subtype-specific therapeutic vulnerabilities in atypical teratoid/rhabdoid tumors (AT/RT).
%J Pharmacological research
%V 213
%@ 1043-6618
%C London
%I Academic Press
%M DKFZ-2025-00386
%P 107660
%D 2025
%Z Volume 213, March 2025, 107660
%X 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.
%K 17-AAG/Tanespimycin (PubChem CID: 6505803) (Other)
%K ABT-199/Venetoclax (PubChem CID: 49846579) (Other)
%K ABT-737 (PubChem CID: 11228183) (Other)
%K Atypical teratoid/rhabdoid tumor (Other)
%K DNA methylation profiling (Other)
%K GDC-0623 (PubChem CID: 42642654) (Other)
%K RNA sequencing (Other)
%K briciclib (PubChem CID: 11248490) (Other)
%K high-throughput drug screening (Other)
%K idasanutlin (PubChem CID: 53358942) (Other)
%K ombrabulin hydrochloride (PubChem CID: 6918404) (Other)
%K targeted therapy (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:39961404
%R 10.1016/j.phrs.2025.107660
%U https://inrepo02.dkfz.de/record/298952