Sensitivity to PPM1D inhibition is regulated by p53. (A) Schematic of CRISPR/Cas9 knockout screen to assess effects of genetic knockout on sensitivity of K562 PPM1D-WT or PPM1D-truncated (TR) cells to daunorubicin or GSK2830371 over a 3-week period. (B-C) Changes in guide RNAs over experiment in PPM1D-WT (B) or PPM1D-TR (C) cells treated with daunorubicin (left) or GSK2830371 (right). Guide RNAs targeting TP53 are highlighted in red. (D) Area under the curve (AUC) calculations for TP53-WT (black) or TP53-mutant (red) cells lines treated with either GSK2830371, daunorubicin, or daunorubicin with GSK2830371 using the PRISM platform (refer to “Methods”). (E) Viability of TC32 (left) or TC71 (right) Ewing sarcoma cells after exposure to radiation and varying doses of GSK2830371. (F) Viability of SIMA (left) or SKNBE2 (right) neuroblastoma cells after exposure to cytotoxic agents and varying doses of GSK2830371.