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BACKGROUND Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Myc-ATRT is driven by the Myc oncogene, which directly controls the intracellular protein synthesis rate. Proteasome inhibitor bortezomib (BTZ) was approved by the Food and Drug Administration as a primary treatment for multiple myeloma. This study aimed to determine whether the upregulation of protein synthesis and proteasome degradation in Myc-ATRTs increases tumor cell sensitivity to BTZ. METHODS We performed differential gene expression and gene set enrichment analysis on matched primary and recurrent patient-derived xenograft (PDX) samples from an infant with ATRT. The expressions of proteasome-encoding genes were compared among this paired model as well as between the 24 human ATRT samples and normal brain tissues. The antitumor effect of BTZ was evaluated in three human Myc-ATRT cell lines (PDX-derived tumor cell line Re1-P6, BT-12, and CHLA-266) and in the orthotopic xenograft models of Re1-P6 cell. RESULTS Concomitant upregulation of the Myc pathway, protein synthesis, and proteasome degradation were identified in recurrent ATRTs. In ATRTs, the proteasome-encoding genes were highly expressed compared with in normal brain tissues, correlated with the malignancy of tumor cells, and were essential for tumor cell survival. BTZ inhibited proliferation and induced apoptosis through the accumulation of p53 in in vitro drug tests. Furthermore, BTZ inhibited tumor growth and prolonged survival in Myc-ATRT orthotopic xenograft mice. CONCLUSIONS Our findings suggest that BTZ may be a promising targeted therapy for Myc-ATRTs.

neuro-oncology

ATRT-01. UPREGULATION OF PROTEIN SYNTHESIS AND PROTEASOME DEGRADATION CONFERS SENSITIVITY TO PROTEASOME INHIBITOR BORTEZOMIB IN MYC-ATYPICAL TERATOID/RHABDOID TUMORS