TY  - JOUR
AU  - Pauck, David
AU  - Picard, Daniel Joseph
AU  - Maue, Mara
AU  - Taban, Kübra
AU  - Marquardt, Viktoria
AU  - Blümel, Lena
AU  - Bartl, Jasmin
AU  - Qin, Nan
AU  - Kubon, Nadezhda
AU  - Schöndorf, Dominik
AU  - Meyer, Frauke-Dorothee
AU  - Theruvath, Johanna
AU  - Mitra, Siddhartha
AU  - Hasselblatt, Martin
AU  - Frühwald, Michael C
AU  - Reifenberger, Guido
AU  - Remke, Marc
TI  - An in vitro pharmacogenomic approach reveals subtype-specific therapeutic vulnerabilities in atypical teratoid/rhabdoid tumors (AT/RT).
JO  - Pharmacological research
VL  - 213
SN  - 1043-6618
CY  - London
PB  - Academic Press
M1  - DKFZ-2025-00386
SP  - 107660
PY  - 2025
N1  - Volume 213, March 2025, 107660
AB  - 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.
KW  - 17-AAG/Tanespimycin (PubChem CID: 6505803) (Other)
KW  - ABT-199/Venetoclax (PubChem CID: 49846579) (Other)
KW  - ABT-737 (PubChem CID: 11228183) (Other)
KW  - Atypical teratoid/rhabdoid tumor (Other)
KW  - DNA methylation profiling (Other)
KW  - GDC-0623 (PubChem CID: 42642654) (Other)
KW  - RNA sequencing (Other)
KW  - briciclib (PubChem CID: 11248490) (Other)
KW  - high-throughput drug screening (Other)
KW  - idasanutlin (PubChem CID: 53358942) (Other)
KW  - ombrabulin hydrochloride (PubChem CID: 6918404) (Other)
KW  - targeted therapy (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:39961404
DO  - DOI:10.1016/j.phrs.2025.107660
UR  - https://inrepo02.dkfz.de/record/298952
ER  -