Our work has a number of clinically relevant implications: MYC/MYCN-amplified GBM, although in a minority of patients, and possibly other MYC/MYCN-amplified brain tumors (e.g., medulloblastoma), should be sensitive to PARPi alone; the combination of ATRi and PARPi does not depend on PARPi sensitivity; and the combination of ATRi and PARPi should be clinically evaluated for GBM, even in the absence of radiation and/or TMZ, such as in recurrent GBM for which there are no current therapies. Here, MYC is linked to medulloblastoma.