TP53 结构-功能关系在转移性去势敏感性前列腺癌中的作用及 APR-246 治疗的影响。
TP53 structure-function relationships in metastatic castrate-sensitive prostate cancer and the impact of APR-246 treatment.
机构信息
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Department of Biochemistry and Molecular Biology, Johns Hopkins University School of Public Health, Baltimore, Maryland, USA.
出版信息
Prostate. 2024 Jan;84(1):87-99. doi: 10.1002/pros.24629. Epub 2023 Oct 9.
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.
目的
尽管在几种恶性肿瘤中进行了大量深入的研究，但 TP53 突变在转移性去势敏感前列腺癌（mCSPC）进展和转移中的表型效应尚不清楚。本研究旨在对 mCSPC 中 TP53 突变的结构-功能和临床影响进行研究。
方法
我们对接受下一代测序且根据 TP53 突变状态和转移负担进行分层的 mCSPC 男性患者进行了一项国际性回顾性研究。临床结局包括用 Kaplan-Meier 和多变量 Cox 回归评估的放射性无进展生存期（rPFS）和总生存期（OS）。我们还利用同源性癌症细胞系来评估 TP53 突变和 APR-246 治疗对体外迁移、侵袭、集落形成和体内肿瘤生长的影响。使用 t 检验和 ANOVA 比较了临床前实验观察结果。
结果
在同时性（vs. 异时性）（20.7% vs. 6.3%，p<0.01）和多发性转移（vs. 寡转移）（14.4% vs. 7.9%，p<0.01）疾病中，显性失活（DN）TP53 突变更为丰富。多变量分析显示，与 TP53 野生型（WT）相比，DN 突变与 rPFS 更差（风险比[HR] = 1.97，95%置信区间[CI]：1.31-2.98）和总生存期[OS]更差（HR = 2.05，95%CI：1.14-3.68）。在体外，与 22Rv1 TP53 WT 细胞相比，22Rv1 TP53 R175H 细胞具有更强的迁移、侵袭、集落形成能力和 RNA 测序分析中细胞运动途径富集。APR-246 的治疗在体外逆转了 TP53 突变的作用，并以剂量依赖性方式抑制了 22Rv1 TP53 R175H 肿瘤的生长。
结论
DN TP53 突变与前列腺癌患者的预后更差和更高的转移潜能相关，APR-246 治疗可逆转这些影响，提示未来可能存在一种治疗途径。
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