Half of all human cancers lose p53 function by missense mutations, with an unknown fraction of these containing p53 in a self-aggregated amyloid-like state. Here we show that a cell-penetrating peptide, ReACp53, designed to inhibit p53 amyloid formation, rescues p53 function in cancer cell lines and in organoids derived from high-grade serous ovarian carcinomas (HGSOC), an aggressive cancer characterized by ubiquitous p53 mutations. Rescued p53 behaves similarly to its wild-type counterpart in regulating target genes, reducing cell proliferation and increasing cell death. Intraperitoneal administration decreases tumor proliferation and shrinks xenografts in vivo. Our data show the effectiveness of targeting a specific aggregation defect of p53 and its potential applicability to HGSOCs. Using p53-mutant, high-grade, serous ovarian carcinoma as model systems, Soragni et al. show that a cell-penetrating peptide designed to inhibit p53 amyloid formation rescues p53 functions and reduces in vivo xenograft growth and metastasis.
Bibliographical noteFunding Information:
We thank Dr. Gregory Lawson for assisting with histological examination of tissues and Dr. Jiaoti Huang for sharing the lentiviral GFP/R175H p53 construct; Dr. Stuart Sievers and Jung-Reem Woo for support with the initial p53 structural characterization; Marco Morselli, Arturo Rinaldi and Dr. Ludmilla Rubbi for help with preparation of the libraries; Dr. Hans-Uwe Simon for helpful discussions. We acknowledge the support of Austin Quach and Farbod Fazlollahi with the MRM assay; the Pasarow Mass Spectrometry Laboratory is supported by NIH grant 1S10RR023718-01A2 . This work was supported by grants from the Pardee Foundation (to A.S.), the NIH ( AG-029430 to D.S.E; R01CA183877 to S.M.), the NIH/ National Center for Advancing Translational Science UCLA CTSI Grant UL1TR000124 (to A.S. and D.S.E.), the American Cancer Society ( RSG-14-217-01-TBG to S.M.), the National Science Foundation ( MCB 0958111 , to D.S.E.), the Jonsson Cancer Center Foundation /UCLA (to S.M. and D.S.E.); the Lynne Cohen Foundation , the Phase One Foundation , the Ovarian Cancer Circle Inspired by Robin Babbini , the Leath L. and Marcia L. Millen Family Fund and the G.O. Discovery Lab Foundation (to S.M.), the HHMI (to D.S.E.) and in part by a VA CDA-2 award (1 K12 BX 001305-01 to S.M.). A.S., L.J. and D.S.E. are inventors on a patent application based on ReACp53 (WO2014182961 A1). A.S. is a consultant for ADRx, Inc.; D.S.E. is a founder, head of the scientific advisory board and equity holder of ADRx, Inc.
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