TP53 structure-function relationships in metastatic castrate-sensitive prostate cancer and the impact of APR-246 treatment.
TP53 structure-function relationships in metastatic castrate-sensitive prostate cancer and the impact of APR-246 treatment.
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转移性去势敏感前列腺癌中的 TP53 结构-功能关系以及 APR-246 治疗的影响。
DOI：
10.1002/pros.24629
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Song,Danie
中科院分区：
文献类型：
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作者：
Hoang,Tung;Sutera,Philip;Nguyen,Triet;Chang,Jinhee;Jagtap,Shreya;Song,Yang;Shetty,AmolC;Chowdhury,DipanwitaD;Chan,Aaron;Carrieri,FrancescaA;Hathout,Lara;Ennis,Ronald;Jabbour,SalmaK;Parikh,Rahul;Molitoris,Jason;Song,Danie
目的尽管对几种恶性肿瘤进行了充分的研究，但TP 53突变在转移性阉割敏感性前列腺癌（mCSPC）进展和转移中的表型影响尚不清楚。我们的特点的结构-功能和临床影响ofTP 53突变mCSPC.Patients and MethodsWe进行了国际回顾性审查的男性mCSPC谁进行了下一代测序和分层根据TP 53突变状态和转移负荷。临床结局包括采用Kaplan-Meier和多变量考克斯回归评估的放射学无进展生存期（rPFS）和总生存期（OS）。我们还利用同基因癌细胞系来评估TP 53突变和APR-246治疗对迁移、侵袭、体外集落形成和体内肿瘤生长的影响。结果显性阴性（DN）TP 53突变在同时性（vs.异时性）（20. 7% vs. 6.3%，p < 0.01）和多转移性（vs.寡转移性）（14. 4% vs. 7.9%，p < 0.01）疾病患者中富集。在多变量分析中，与TP 53野生型（WT）相比，DN突变与更差的rPFS（风险比[HR] = 1.97，95%置信区间[CI]：1.31-2.98）和总生存期[OS]（HR = 2.05，95% CI：1.14-3.68）相关。体外实验结果显示，22 Rv 1 TP 53 R175 H细胞的迁移、侵袭、集落形成能力和细胞运动途径的富集能力均强于22 Rv 1 TP 53 WT细胞。结论DNTP 53基因突变与前列腺癌患者预后差、转移潜能高有关，APR-246治疗可逆转TP 53基因突变的效应，提示APR-246治疗前列腺癌可能是一种潜在的治疗途径。
PurposeDespite well‐informed work in several malignancies, the phenotypic effects ofTP53mutations in metastatic castration‐sensitive prostate cancer (mCSPC) progression and metastasis are not clear. We characterized the structure–function and clinical impact ofTP53mutations in mCSPC.Patients and MethodsWe performed an international retrospective review of men with mCSPC who underwent next‐generation sequencing and were stratified according toTP53mutational 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 ofTP53mutations and APR‐246 treatment on migration, invasion, colony formation in vitro, and tumor growth in vivo. Preclinical experimental observations were compared usingt‐tests and ANOVA.ResultsDominant‐negative (DN)TP53mutations 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 toTP53wild type (WT). In vitro, 22Rv1TP53 R175Hcells possessed stronger migration, invasion, colony formation ability, and cellular movement pathway enrichment in RNA sequencing analysis compared to 22Rv1TP53WT cells. Treatment with APR‐246 reversed the effects of TP53 mutations in vitro and inhibited 22Rv1TP53 R175Htumor growth in vivo in a dosage‐dependent manner.ConclusionsDNTP53mutations 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.