We show that MYC or MYCN amplification in patient-derived glioblastoma stem-like cells (GSCs) generates sensitivity to PARPi via Myc-mediated transcriptional repression of CDK18, while most tumors without amplification are not sensitive.
NAMPT inhibitors were potently cytotoxic, inducing apoptosis and significantly extended the survival of mice bearing MYCN-amplified patient-derived glioblastoma orthotopic xenografts.
This finding also confirms the importance of impairment of the MYC/MAX/MXD1 axis in the development of aggressive neural tumors, because MYCN overexpression is an established genetic hallmark of malign neuroblastoma, and it is likely that MXI1 plays a relevant role in the development of medulloblastoma and glioblastoma.
Gene amplification and rearrangements are discussed through review of recent work on the N-myc gene in neuroblastoma and the epidermal growth factor receptor (EGFR) gene in glioblastoma.