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TP53 structure-function relationships in metastatic castrate-sensitive prostate cancer and the impact of APR-246 treatment.
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.
Affiliation
  • Hoang T; Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Sutera P; Department of Biochemistry and Molecular Biology, Johns Hopkins University School of Public Health, Baltimore, Maryland, USA.
  • Nguyen T; Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Chang J; Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Jagtap S; Department of Biochemistry and Molecular Biology, Johns Hopkins University School of Public Health, Baltimore, Maryland, USA.
  • Song Y; Department of Radiation Oncology, Division of Translational Radiation Sciences, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland, USA.
  • Shetty AC; Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Chowdhury DD; Department of Radiation Oncology, Division of Translational Radiation Sciences, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland, USA.
  • Chan A; Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Carrieri FA; Department of Radiation Oncology, Division of Translational Radiation Sciences, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland, USA.
  • Hathout L; Department of Radiation Oncology, Division of Translational Radiation Sciences, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland, USA.
  • Ennis R; Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
  • Jabbour SK; Department of Radiation Oncology, Division of Translational Radiation Sciences, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland, USA.
  • Parikh R; Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
  • Molitoris J; Department of Radiation Oncology, Division of Translational Radiation Sciences, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland, USA.
  • Song DY; Department of Radiation Oncology, Division of Translational Radiation Sciences, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland, USA.
  • DeWeese T; Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Marchionni L; Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA.
  • Ren L; Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA.
  • Sawant A; Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA.
  • Simone N; Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA.
  • Lafargue A; Department of Radiation Oncology, Division of Translational Radiation Sciences, University of Maryland Baltimore, School of Medicine, Baltimore, Maryland, USA.
  • Van Der Eecken K; Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Bunz F; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Ost P; Department of Urology, James Buchanan Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Tran PT; Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Deek MP; Department of Urology, James Buchanan Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Prostate ; 84(1): 87-99, 2024 Jan.
Article in En | MEDLINE | ID: mdl-37812042
ABSTRACT

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 < 0.01) and polymetastatic (vs. oligometastatic) (14.4% vs. 7.9%, p < 0.01) disease. On multivariable analysis, DN mutations were associated with worse rPFS (hazards ratio [HR] = 1.97, 95% confidence interval [CI] 1.31-2.98) and overall survival [OS] (HR = 2.05, 95% CI 1.14-3.68) compared to TP53 wild type (WT). In vitro, 22Rv1 TP53 R175H cells possessed stronger migration, invasion, colony formation ability, and cellular movement pathway enrichment in RNA sequencing analysis compared to 22Rv1 TP53 WT cells. Treatment with APR-246 reversed the effects of TP53 mutations in vitro and inhibited 22Rv1 TP53 R175H tumor growth in vivo in a dosage-dependent manner.

CONCLUSIONS:

DN TP53 mutations correlated with worse prognosis in prostate cancer patients and higher metastatic potential, which could be counteracted by APR-246 treatment suggesting a potential future therapeutic avenue.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Prostatic Neoplasms, Castration-Resistant Type of study: Diagnostic_studies Limits: Humans / Male Language: En Journal: Prostate Year: 2024 Document type: Article Affiliation country: Country of publication:
Fulltext
Add to My VHL
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PubMed Links
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Prostatic Neoplasms, Castration-Resistant Type of study: Diagnostic_studies Limits: Humans / Male Language: En Journal: Prostate Year: 2024 Document type: Article Affiliation country: Country of publication: