We demonstrate that DNA-damaging therapies (i.e., the standard of care for GBM) rapidly ablate the MCL-1 block via p53-dependent induction of PUMA, which subsequently binds and sequesters MCL-1, creating a sole survival dependency on BCL-XL in GBM lacking genetic alterations in the p53 signaling pathway. Here, BCL2L1 is linked to glioblastoma.