Abstract Atypical teratoid/rhabdoid tumor (AT/RT) is a highly aggressive embryonal brain tumor in infants and toddlers. Due to its dismal prognosis with 5-year overall survival rates of 35 % in high-risk groups multimodal therapy is the current standard of care comprising maximum safe surgical resection, chemotherapy and, if justifiable, radiotherapy. AT/RT is driven by biallelic inactivation of the SMARCB1 gene or, much rarer, SMARCA4. Recent epigenetic investigations have identified the molecular subtypes of AT/RT, AT/RT-TYR, -SHH and -MYC, along with the activation of subtype-specific super enhancers as drivers of tumorigenesis. These findings did not enable targeted therapy of AT/RT, yet, and aggressive therapy frequently leaves survivors of AT/RT with life-long sequelae. We performed an in vitro drug screening study using a library of 768 established anti-cancer drugs and those in the late stages of drug development. High-resolution dose-response profiles of 13 AT/RT cell lines indicate specific growth inhibition of AT/RT cell lines using mitogen-activated protein kinase kinase (MEK) inhibitors and mouse double minute 2 homolog (MDM2) inhibitors when compared to cell lines derived from other highly malignant brain tumors. Moreover, through assigning molecular subtypes to AT/RT cell lines by means of DNA methylation profiling and RNASeq-based expression profiling, we discovered subtype-dependent vulnerabilities. While B-cell lymphoma 2 (BCL2) inhibitors and heat shock protein 90 (HSP90) inhibitors target AT/RT-SHH cell lines, we revealed preferential growth inhibition of AT/RT-MYC cell lines using microtubule inhibitors, kinesin spindle protein (KSP) inhibitors and an eukaryotic translation initiation factor 4E (eIF4E) inhibitor. These findings may be translated into novel targeted strategies for the treatment of AT/RT to reduce not only disease-related, but also therapy-induced mortality, specifically in the setting of disease relapse.
Pauck et al. (Fri,) studied this question.