TP53 structure–function relationships in metastatic castrate‐sensitive prostate cancer and the impact of APR‐246 treatment

Purpose Despite well‐informed work in several malignancies, the phenotypic effects of TP53 mutations in metastatic castration‐sensitive prostate cancer (mCSPC) progression and metastasis are not clear. We characterized the structure–function and clinical impact of TP53 mutations in mCSPC. Patients a...

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Bibliographic Details
Published in:The Prostate 2024-01, Vol.84 (1), p.87-99
Main Authors: Hoang, Tung, Sutera, Philip, Nguyen, Triet, Chang, Jinhee, Jagtap, Shreya, Song, Yang, Shetty, Amol C., Chowdhury, Dipanwita D., Chan, Aaron, Carrieri, Francesca A., Hathout, Lara, Ennis, Ronald, Jabbour, Salma K., Parikh, Rahul, Molitoris, Jason, Song, Daniel Y., DeWeese, Theodore, Marchionni, Luigi, Ren, Lei, Sawant, Amit, Simone, Nicole, Lafargue, Audrey, Van Der Eecken, Kim, Bunz, Fred, Ost, Piet, Tran, Phuoc T., Deek, Matthew P.
Format: Article
Language:English
Subjects:
APR‐246
Castration
Cell migration
Colonies
dominant‐negative TP53 mutations
Humans
invasion
Male
Malignancy
mCSPC
Medical prognosis
Metastases
Metastasis
Mutation
p53 Protein
Patients
Prognosis
Progression-Free Survival
Prostate cancer
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - genetics
Prostatic Neoplasms - pathology
Prostatic Neoplasms, Castration-Resistant - drug therapy
Prostatic Neoplasms, Castration-Resistant - genetics
Prostatic Neoplasms, Castration-Resistant - pathology
Sequence analysis
Structure-Activity Relationship
Structure-function relationships
TP53
Tumor cell lines
Tumor Suppressor Protein p53 - genetics
Tumors
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Summary:Purpose Despite well‐informed work in several malignancies, the phenotypic effects of TP53 mutations in metastatic castration‐sensitive prostate cancer (mCSPC) progression and metastasis are not clear. We characterized the structure–function and clinical impact of TP53 mutations in mCSPC. Patients and Methods We performed an international retrospective review of men with mCSPC who underwent next‐generation sequencing and were stratified according to TP53 mutational status and metastatic burden. Clinical outcomes included radiographic progression‐free survival (rPFS) and overall survival (OS) evaluated with Kaplan–Meier and multivariable Cox regression. We also utilized isogenic cancer cell lines to assess the effect of TP53 mutations and APR‐246 treatment on migration, invasion, colony formation in vitro, and tumor growth in vivo. Preclinical experimental observations were compared using t‐tests and ANOVA. Results Dominant‐negative (DN) TP53 mutations were enriched in patients with synchronous (vs. metachronous) (20.7% vs. 6.3%, p 
ISSN:0270-4137
1097-0045
1097-0045
DOI:10.1002/pros.24629