Therapeutic targeting of mutant p53 in pediatric acute lymphoblastic leukemia.

Alterations of the tumor suppressor gene are found in different cancers, in particular in carcinomas of adults. In pediatric acute lymphoblastic leukemia (ALL), mutations are infrequent but enriched at relapse. As in most cancers, mainly DNA-binding domain missense mutations are found, resulting in accumulation of mutant p53, poor therapy response, and inferior outcome. Different strategies to target mutant p53 have been developed including reactivation of p53's wildtype function by the small molecule APR-246. We investigated mutations in cell lines and 62 B-cell precursor ALL samples and evaluated the activity of APR-246 in -mutated or wildtype ALL. We identified cases with missense mutations, high (mutant) p53 expression and insensitivity to the DNA-damaging agent doxorubicin. In -mutated ALL, APR-246 induced apoptosis showing strong anti-leukemia activity. APR-246 restored mutant p53 to its wildtype conformation, leading to pathway activation with induction of transcriptional targets and re-sensitization to genotoxic therapy and In addition, induction of oxidative stress contributed to APR-246-mediated cell death. In a preclinical model of patient-derived -mutant ALL, APR-246 reduced leukemia burden and synergized strongly with the genotoxic agent doxorubicin, leading to superior leukemia-free survival Thus, targeting mutant p53 by APR-246, restoring its tumor suppressive function, seems to be an effective therapeutic strategy for this high-risk group of -mutant ALL.