p53 prophylactic therapy for cancer prevention.

Germline mutations in the tumor suppressor TP53 lead to cancer predisposition, as seen in Li-Fraumeni syndrome (LFS). Currently, no strategies exist to delay or prevent cancer development in this population. Our work is based on the hypothesis that modulating wild-type p53 levels could serve as a prophylactic approach to mitigate cancer risk. By introducing a third copy of Trp53, either constitutively or in an inducible manner in adulthood, we demonstrate that tumor development is delayed, and mice live longer without observable side effects in both the Eu-myc lymphoma and LFS models. Mechanistically, Trp53 loss of heterozygosity is reduced in the LFS model, accompanied by an enhanced p53 transcriptional response. Our findings therefore provide genetic evidence supporting this approach, which could be leveraged to identify compounds that modulate p53 levels and benefit LFS carriers and other cancer-prone populations with reduced p53 activity.