TP53 structure–function relationships in metastatic castrate‐sensitive prostate cancer and the impact of APR‐246 treatment-Reference-Cited by-同舟云学术

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

Published:2023-10-09 Issue:1 Volume:84 Page:87-99
ISSN:0270-4137
Container-title:The Prostate
language:en
Short-container-title:The Prostate

Author:

Hoang Tung¹²^ORCID,Sutera Philip¹,Nguyen Triet¹²³,Chang Jinhee¹³^ORCID,Jagtap Shreya¹³,Song Yang³⁴,Shetty Amol C.³⁴,Chowdhury Dipanwita D.³,Chan Aaron³,Carrieri Francesca A.¹,Hathout Lara⁵,Ennis Ronald⁵,Jabbour Salma K.⁵,Parikh Rahul⁵^ORCID,Molitoris Jason³,Song Daniel Y.¹⁶⁷,DeWeese Theodore¹⁷,Marchionni Luigi⁸^ORCID,Ren Lei³,Sawant Amit³,Simone Nicole⁹,Lafargue Audrey¹³^ORCID,Van Der Eecken Kim¹⁰,Bunz Fred¹⁷,Ost Piet¹¹¹²,Tran Phuoc T.¹³⁶⁷,Deek Matthew P.⁵

Affiliation:

1. Department of Radiation Oncology and Molecular Radiation Sciences Johns Hopkins University School of Medicine Baltimore Maryland USA

2. Department of Biochemistry and Molecular Biology Johns Hopkins University School of Public Health Baltimore Maryland USA

3. Department of Radiation Oncology, Division of Translational Radiation Sciences University of Maryland Baltimore, School of Medicine Baltimore Maryland USA

4. Institute for Genome Sciences University of Maryland School of Medicine Baltimore Maryland USA

5. Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School Rutgers University New Brunswick New Jersey USA

6. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University School of Medicine Baltimore Maryland USA

7. Department of Urology, James Buchanan Urological Institute Johns Hopkins University School of Medicine Baltimore Maryland USA

8. Weill Cornell Medicine New York New York USA

9. Department of Radiation Oncology, Sidney Kimmel Cancer Center Thomas Jefferson University Philadelphia Pennsylvania USA

10. Department of Pathology Ghent University Hospital, Cancer Research Institute (CRIG) Ghent Belgium

11. Department of Radiation Oncology Iridium Network Antwerp Belgium

12. Department of Human Structure and Repair Ghent University Ghent Belgium

Abstract

AbstractPurposeDespite 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 MethodsWe 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.ResultsDominant‐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.ConclusionsDN 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.

Publisher

Wiley

Subject

Urology,Oncology

Link

https://onlinelibrary.wiley.com/doi/pdf/10.1002/pros.24629

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