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Restoration of the Tumor Suppressor Function of Y220C-Mutant p53 in vitro by Rezatapopt (PC14586), a Small Molecule Reactivator [in vitro]

ABSTRACT: Restoration of the tumor suppressor function of tumor-associated p53 mutants, including tumors harboring the TP53 Y220C mutation, has posed a significant challenge and remains an attractive target for therapeutic discovery. Here, we describe a clinical candidate Rezatapopt (PC14586) designed to stabilize the p53 Y220C mutant protein and restore wild-type (WT) p53 function. PC14586 induced global gene expression changes in the cell lines harboring the TP53 Y220C mutation (NUGC-3 and T3M-4) but not in cells lacking p53 Y220C-mutant protein (NUGC-3 KO and SJSA-1). Extensive transcriptomics analysis of cells harboring the TP53 Y220C mutation following PC14586 treatment revealed the induction of p53 direct target genes, including protein-coding genes and long non-coding RNAs (lncRNAs), and repression of cell cycle progression-associated genes in a distinct temporal pattern. Our data demonstrate that PC14586 administration inhibited cell proliferation in vitro via the induction of WT p53 transcriptional signatures, including a sustained transcriptional repression of genes involved in cell cycle regulation. Following these investigations and additional in vivo studies, rezatapopt (PC14586) was identified as a clinical candidate and is currently being evaluated in the registrational Phase 2 PYNNACLE study.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276223 | GEO | 2025/02/03

REPOSITORIES: GEO

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Restoration of the Tumor Suppressor Function of Y220C-Mutant p53 in vivo by Rezatapopt (PC14586), a Small Molecule Reactivator [in vivo]

Project description:Restoration of the tumor suppressor function of tumor-associated p53 mutants, including tumors harboring the TP53 Y220C mutation, has posed a significant challenge and remains an attractive target for therapeutic discovery. Here, we describe a clinical candidate Rezatapopt (PC14586) designed to stabilize the p53 Y220C mutant protein and restore wild-type (WT) p53 function. Extensive transcriptomics analysis of NUGC-3 xenografted tumors harboring the TP53 Y220C mutation following PC14586 treatment revealed the induction of p53 direct target genes, including protein-coding genes and long non-coding RNAs (lncRNAs), and repression of cell cycle progression-associated genes in a distinct temporal pattern. Our data demonstrate that PC14586 administration inhibited tumor growth in vivo via the induction of WT p53 transcriptional signatures, including a sustained transcriptional repression of genes involved in cell cycle regulation. Following these investigations, rezatapopt (PC14586) was identified as a clinical candidate and is currently being evaluated in the registrational Phase 2 PYNNACLE study.

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The Evaluation of PC14586 in Patients With Advanced Solid Tumors Harboring a p53 Y220C Mutation (PYNNACLE)

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Project description:The TP53 c.359A>G mutation severely impairs expression of the major TP53 transcript variant encoding p53 K120R by creating a new splicing donor site. Antisense morpholino oligomer (AMO) targeting the mutation site restored normal splicing and expression of the major variant. Despite the recovery of mutant TP53 mRNA levels, the functional restoration as the tumor suppressor of p53 K120R was unclear. Given that p53 exerts its tumor suppressor function through regulation of target genes that mediate growth arrest or apoptosis, the p53 K120R mutant exhibits impaired transcriptional regulation of CDKN1A, a key target gene in growth arrest, while maintaining normal induction of the pro-apoptotic BBC3 gene. Consequently, the p53 K120R mutant protein demonstrates a phenotype characterized by defective cell growth arrest but retained apoptotic induction capacity, suggesting that the p53 K120R mutant protein may retain some tumor suppressor functionality. In addition, Lysine 120 provides a critical acetylation site linked to p53 activation. Although other studies of the oncogenic effects of p53 K120R highlight the relevance of acetylation for tumor suppression, our findings indicate that targeting mutant TP53 mRNA is a prerequisite for restoration of p53 function. In particular, despite the presence of mutations, it showed sufficient corrective effect to restore p53 functions, including apoptosis induction. In conclusion, this study highlights the potential of AMO-mediated splice correction as a therapeutic approach for TP53 mutations.

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p53 ChIP-seq in Nutlin-treated HCT116, MCF7, and SJSA cell lines

Project description:To identify genomic loci occupied by p53, we performed p53 ChIP-seq analysis of colorectal carcinoma cell line HCT116, breast carcinoma line MCF7, and osteosarcoma line SJSA treated with MDM2 inhibitor Nutlin.

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RNA sequencing of tumors from PPM1D transgenic mouse model

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TP53 c.1000G>C; p.G334R is an Ashkenazi Jewish predominant mutation associated with a low penetrance Li-Fraumeni Syndrome

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