The p53 transcription factor is a master regulator of cellular stress responses inhibited by repressors such as MDM2 and the phosphatase PPM1D. Activation of p53 with pharmacological inhibitors of its repressors is being tested in clinical trials for cancer therapy, but efficacy has been limited by poor induction of tumor cell death. We demonstrate that dual inhibition of MDM2 and PPM1D induces apoptosis in multiple cancer cell types via amplification of the p53 transcriptional program through the eIF2α-ATF4 pathway. PPM1D inhibition induces phosphorylation of eIF2α, ATF4 accumulation, and ATF4-dependent enhancement of p53-dependent transactivation upon MDM2 inhibition. Dual inhibition of p53 repressors depletes heme and induces HRI-dependent eIF2α phosphorylation. Pharmacological induction of eIF2α phosphorylation synergizes with MDM2 inhibition to induce cell death and halt tumor growth in mice. These results demonstrate that PPM1D inhibits both the p53 network and the integrated stress response controlled by eIF2α-ATF4, with clear therapeutic implications.

p53 转录因子是细胞应激反应的主要调节因子，可被 MDM2 和磷酸酶 PPM1D 等阻遏物抑制。癌症治疗的临床试验正在测试用其阻遏物的药理学抑制剂激活p53，但由于肿瘤细胞死亡诱导不佳，疗效受到限制。我们证明，MDM2 和 PPM1D 的双重抑制可通过 eIF2α-ATF4 途径扩增 p53 转录程序，从而诱导多种癌细胞类型凋亡。 PPM1D 抑制可诱导 eIF2α 磷酸化、ATF4 积累，以及 MDM2 抑制后 ATF4 依赖性 p53 依赖性反式激活的增强。 p53 阻遏物的双重抑制会消耗血红素并诱导 HRI 依赖性 eIF2α 磷酸化。 eIF2α 磷酸化的药理学诱导与 MDM2 抑制协同作用，诱导小鼠细胞死亡并阻止肿瘤生长。这些结果表明，PPM1D 抑制 p53 网络和 eIF2α-ATF4 控制的综合应激反应，具有明确的治疗意义。