Open Access

David Pauck, Daniel Picard, Mara Maue, Kübra Taban, Viktoria Marquardt, Lena Blümel, Jasmin Bartl, Nan Qin, Nadezhda Kubon, Dominik Schöndorf, Frauke-Dorothee Meyer, Johanna Theruvath, Siddhartha Mitra, Martin Hasselblatt, Michael C. Frühwald, Guido Reifenberger, Marc Remke

• 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 andAtypical 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.…