The ReACp53 peptide reactivates p53 and reduces the growth of p53-mutant ovarian carcinomas.

  • Major finding: The ReACp53 peptide reactivates p53 and reduces the growth of p53-mutant ovarian carcinomas.

  • Approach: ReACp53 was rationally designed from the LTIITLE amyloid adhesive segment of p53 to block aggregation.

  • Impact: Inhibiting p53 aggregation is a promising strategy for treating p53-mutant tumors.

The essential tumor suppressor p53 is inactivated by mutations in over half of human tumors, with the highest mutation rate occurring in high-grade serous ovarian carcinomas (HGSOC). One mechanism of p53 inactivation is through mutations that partially unfold the protein, resulting in p53 aggregates. Currently, no therapies are available to restore p53 function. Soragni and colleagues developed a cell-permeable peptide inhibitor of p53 aggregation, ReACp53, to determine if blocking aggregation could restore p53 function and reduce tumor growth. The rational design was based on the X-ray structure of the LTIITLE amyloid adhesive segment of p53, which is sufficient for p53 aggregation. ReACp53 prevented p53 aggregation in vitro and in cells from patients with HGSOC. In HGSOC cell lines, ReACp53 induced cell death by apoptosis and necroptosis, and blocked cell-cycle progression. In a three-dimensional culture system, human primary uterine fibroblasts expressing dominant-negative p53R175H were responsive to ReACp53 and exhibited reduced growth and increased apoptosis. Further, in organoid cultures, ReACp53 induced cell death in HGSOC cells with aggregating mutant p53, but not in cells with normally folded wild-type p53. RNA sequencing of organoids indicated that p53 targets were upregulated by ReACp53 treatment, including the genes encoding p21, GADD45B, PUMA, THBS1, NOXA, and DRAM1, as well as genes involved in cell proliferation and cell death. In vivo, ReACp53 was well tolerated and stable, with approximately 20% of the peak ReACp53 still present in the circulation after 24 hours, and reduced tumor volume in HGSOC xenograft models and a physiologic intraperitoneal disseminated disease model. Altogether, these data indicate that ReACp53 blocks p53 aggregation, promotes p53 reactivation, and reduces HGSOC growth and viability. This suggests that inhibiting the aggregation of p53 may be a viable strategy to reactivate it and suppress tumor growth in patients with HGSOC and other p53-mutant tumors.

Soragni A, Janzen DM, Johnson LM, Lindgren AG, Nguyen AT-Q, Tiourin E, et al. A designed inhibitor of p53 aggregation rescues p53 tumor suppression in ovarian carcinomas. Cancer Cell 2016;29:90–103.

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