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; 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; Matthew P. Deek

doi:10.1002/pros.24629

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, Lara Hathout, Ronald Ennis, Salma K. Jabbour, Rahul Parikh, Jason Molitoris, Daniel Y. Song, Theodore DeWeese, Luigi Marchionni, Lei Ren, Amit SawantNicole Simone, Audrey Lafargue, Kim Van Der Eecken, Fred Bunz, Piet Ost, Phuoc T. Tran, Matthew P. Deek

School of Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	87-99
Number of pages	13
Journal	Prostate
Volume	84
Issue number	1
DOIs	https://doi.org/10.1002/pros.24629
State	Published - Jan 2024

Keywords

APR-246
TP53
dominant-negative TP53 mutations
invasion
mCSPC
metastasis

ASJC Scopus subject areas

Oncology
Urology

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10.1002/pros.24629

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Hoang, T., Sutera, P., Nguyen, T., Chang, J., Jagtap, S., Song, Y., Shetty, A. C., Chowdhury, D. D., Chan, A., Carrieri, F. A., Hathout, L., Ennis, R., Jabbour, S. K., Parikh, R., Molitoris, J., Song, D. Y., DeWeese, T., Marchionni, L., Ren, L., ... 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

Hoang, T, Sutera, P, Nguyen, T, Chang, J, Jagtap, S, Song, Y, Shetty, AC, Chowdhury, DD, Chan, A, Carrieri, FA, Hathout, L, Ennis, R, Jabbour, SK, Parikh, R, Molitoris, J, Song, DY , DeWeese, T, Marchionni, L, Ren, L, Sawant, A, Simone, N, Lafargue, A, Van Der Eecken, K, Bunz, F, Ost, P, Tran, PT & Deek, MP 2024, '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. https://doi.org/10.1002/pros.24629

@article{36c01ba53a3c49599ef1bc3eda4a436b,

title = "TP53 structure–function relationships in metastatic castrate-sensitive prostate cancer and the impact of APR-246 treatment",

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 = "APR-246, TP53, dominant-negative TP53 mutations, invasion, mCSPC, metastasis",

author = "Tung Hoang and Philip Sutera and Triet Nguyen and Jinhee Chang and Shreya Jagtap and Yang Song and Shetty, {Amol C.} and Chowdhury, {Dipanwita D.} and Aaron Chan and Carrieri, {Francesca A.} and Lara Hathout and Ronald Ennis and Jabbour, {Salma K.} and Rahul Parikh and Jason Molitoris and Song, {Daniel Y.} and Theodore DeWeese and Luigi Marchionni and Lei Ren and Amit Sawant and Nicole Simone and Audrey Lafargue and {Van Der Eecken}, Kim and Fred Bunz and Piet Ost and Tran, {Phuoc T.} and Deek, {Matthew P.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. The Prostate published by Wiley Periodicals LLC.",

year = "2024",

month = jan,

doi = "10.1002/pros.24629",

language = "English (US)",

volume = "84",

pages = "87--99",

journal = "Prostate",

issn = "0270-4137",

publisher = "John Wiley and Sons Inc.",

number = "1",

}

TY - JOUR

T1 - TP53 structure–function relationships in metastatic castrate-sensitive prostate cancer and the impact of APR-246 treatment

AU - Hoang, Tung

AU - Sutera, Philip

AU - Nguyen, Triet

AU - Chang, Jinhee

AU - Jagtap, Shreya

AU - Song, Yang

AU - Shetty, Amol C.

AU - Chowdhury, Dipanwita D.

AU - Chan, Aaron

AU - Carrieri, Francesca A.

AU - Hathout, Lara

AU - Ennis, Ronald

AU - Jabbour, Salma K.

AU - Parikh, Rahul

AU - Molitoris, Jason

AU - Song, Daniel Y.

AU - DeWeese, Theodore

AU - Marchionni, Luigi

AU - Ren, Lei

AU - Sawant, Amit

AU - Simone, Nicole

AU - Lafargue, Audrey

AU - Van Der Eecken, Kim

AU - Bunz, Fred

AU - Ost, Piet

AU - Tran, Phuoc T.

AU - Deek, Matthew P.

PY - 2024/1

Y1 - 2024/1

N2 - 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.

AB - 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.

KW - APR-246

KW - TP53

KW - dominant-negative TP53 mutations

KW - invasion

KW - mCSPC

KW - metastasis

UR - http://www.scopus.com/inward/record.url?scp=85173965877&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85173965877&partnerID=8YFLogxK

U2 - 10.1002/pros.24629

DO - 10.1002/pros.24629

M3 - Article

C2 - 37812042

AN - SCOPUS:85173965877

SN - 0270-4137

VL - 84

SP - 87

EP - 99

JO - Prostate

JF - Prostate

IS - 1

ER -

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

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