Decitabine induces IRF7-mediated immune responses in p53-mutated triple-negative breast cancer: a clinical and translational study

被引：1

作者：

Wang, Haoyu ^{[1
]}

Wang, Zhengyuan ^{[2
]}

Wang, Zheng ^{[1
]}

Li, Xiaoyang ^{[3
]}

Li, Yuntong ^{[2
]}

Yan, Ni ^{[2
]}

Wu, Lili ^{[2
]}

Liang, Ying ^{[2
]}

Wu, Jiale ^{[2
]}

Song, Huaxin ^{[2
]}

Qu, Qing ^{[1
]}

Huang, Jiahui ^{[1
]}

Chang, Chunkang ^{[4
]}

Shen, Kunwei ^{[1
]}

Chen, Xiaosong ^{[1
]}

Lu, Min ^{[2
]}

机构：

[1] Shanghai Jiao Tong Univ, Comprehens Breast Hlth Ctr, Dept Gen Surg, Ruijin Hosp,Sch Med, Shanghai 200025, Peoples R China

[2] Shanghai Jiao Tong Univ, Shanghai Inst Hematol, Natl Res Ctr Translat Med Shanghai, State Key Lab Med Genom,Ruijin Hosp,Sch Med, Shanghai, Peoples R China

[3] Shanghai Jiao Tong Univ, Shanghai Inst Hematol, Dept Hematol, Ruijin Hosp,Sch Med, Shanghai 200025, Peoples R China

[4] Shanghai Jiao Tong Univ, Dept Hematol, Affiliated Peoples Hosp 6, Shanghai 200025, Peoples R China

来源：

FRONTIERS OF MEDICINE | 2024年 / 18卷 / 02期

基金：

中国国家自然科学基金;

关键词：

p53; mutation; triple-negative breast cancer; decitabine; DNMT1; IRF7; innate immune response; DNA METHYLTRANSFERASE; PHASE-II; TP53; MUTATIONS; OVARIAN-CANCER; P53; CARBOPLATIN; PLATINUM; METHYLATION; COMBINATION; TRIAL;

D O I：

10.1007/s11684-023-1016-8

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

p53 is mutated in half of cancer cases. However, no p53-targeting drugs have been approved. Here, we reposition decitabine for triple-negative breast cancer (TNBC), a subtype with frequent p53 mutations and extremely poor prognosis. In a retrospective study on tissue microarrays with 132 TNBC cases, DNMT1 overexpression was associated with p53 mutations (P = 0.037) and poor overall survival (OS) (P = 0.010). In a prospective DEciTabinE and Carboplatin in TNBC (DETECT) trial (NCT03295552), decitabine with carboplatin produced an objective response rate (ORR) of 42% in 12 patients with stage IV TNBC. Among the 9 trialed patients with available TP53 sequencing results, the 6 patients with p53 mutations had higher ORR (3/6 vs. 0/3) and better OS (16.0 vs. 4.0 months) than the patients with wild-type p53. In a mechanistic study, isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher DNMT1 expression and decitabine sensitivity than the cell line with wild-type p53. In the DETECT trial, decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line (upregulation by 16-fold) and the most responsive patient with TNBC. Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.

引用

页码：357 / 374

页数：18