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

Tung Hoang, Philip Sutera, Triet Nguyen, Jinhee Chang, Shreya Jagtap, Yang Song, Amol C. Shetty, Dipanwita D. Chowdhury, Aaron Chan, Francesca A. Carrieri, et al.
(2024) PROSTATE. 84(1). p.87-99
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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.
Keywords
TP53, metastasis, mCSPC, invasion, dominant-negative TP53 mutations, APR-246

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MLA
Hoang, Tung, et al. “TP53 Structure-Function Relationships in Metastatic Castrate-Sensitive Prostate Cancer and the Impact of APR-246 Treatment.” PROSTATE, vol. 84, no. 1, 2024, pp. 87–99, doi:10.1002/pros.24629.
APA
Hoang, T., Sutera, P., Nguyen, T., Chang, J., Jagtap, S., Song, Y., … Deek, M. P. (2024). TP53 structure-function relationships in metastatic castrate-sensitive prostate cancer and the impact of APR-246 treatment. PROSTATE, 84(1), 87–99. https://doi.org/10.1002/pros.24629
Chicago author-date
Hoang, Tung, Philip Sutera, Triet Nguyen, Jinhee Chang, Shreya Jagtap, Yang Song, Amol C. Shetty, et al. 2024. “TP53 Structure-Function Relationships in Metastatic Castrate-Sensitive Prostate Cancer and the Impact of APR-246 Treatment.” PROSTATE 84 (1): 87–99. https://doi.org/10.1002/pros.24629.
Chicago author-date (all authors)
Hoang, Tung, Philip Sutera, Triet Nguyen, Jinhee Chang, Shreya Jagtap, Yang Song, Amol C. Shetty, Dipanwita D. Chowdhury, Aaron Chan, Francesca A. Carrieri, Lara Hathout, Ronald Ennis, Salma K. Jabbour, Rahul Parikh, Jason Molitoris, Daniel Y. Song, Theodore DeWeese, Luigi Marchionni, Lei Ren, Amit Sawant, Nicole Simone, Audrey Lafargue, Kim Van der Eecken, Fred Bunz, Piet Ost, Phuoc T. Tran, and Matthew P. Deek. 2024. “TP53 Structure-Function Relationships in Metastatic Castrate-Sensitive Prostate Cancer and the Impact of APR-246 Treatment.” PROSTATE 84 (1): 87–99. doi:10.1002/pros.24629.
Vancouver
1.
Hoang T, Sutera P, Nguyen T, Chang J, Jagtap S, Song Y, et al. TP53 structure-function relationships in metastatic castrate-sensitive prostate cancer and the impact of APR-246 treatment. PROSTATE. 2024;84(1):87–99.
IEEE
[1]
T. Hoang et al., “TP53 structure-function relationships in metastatic castrate-sensitive prostate cancer and the impact of APR-246 treatment,” PROSTATE, vol. 84, no. 1, pp. 87–99, 2024.
@article{01HY0E616C317GT2V7XAAX77VF,
  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.}},
  author       = {{Hoang, Tung and Sutera, Philip and  Nguyen, Triet and  Chang, Jinhee and  Jagtap, Shreya and  Song, Yang and  Shetty, Amol C. and  Chowdhury, Dipanwita D. and  Chan, Aaron and  Carrieri, Francesca A. and  Hathout, Lara and  Ennis, Ronald and  Jabbour, Salma K. and  Parikh, Rahul and  Molitoris, Jason and  Song, Daniel Y. and  DeWeese, Theodore and  Marchionni, Luigi and  Ren, Lei and  Sawant, Amit and  Simone, Nicole and  Lafargue, Audrey and Van der Eecken, Kim and  Bunz, Fred and Ost, Piet and Tran, Phuoc T. and Deek, Matthew P.}},
  issn         = {{0270-4137}},
  journal      = {{PROSTATE}},
  keywords     = {{TP53,metastasis,mCSPC,invasion,dominant-negative TP53 mutations,APR-246}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{87--99}},
  title        = {{TP53 structure-function relationships in metastatic castrate-sensitive prostate cancer and the impact of APR-246 treatment}},
  url          = {{http://doi.org/10.1002/pros.24629}},
  volume       = {{84}},
  year         = {{2024}},
}
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