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

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

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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.

p53 mutationtriple-negative breast cancerdecitabineDNMT1IRF7innate immune response

Haoyu Wang、Zhengyuan Wang、Zheng Wang、Xiaoyang Li、Yuntong Li、Ni Yan、Lili Wu、Ying Liang、Jiale Wu、Huaxin Song、Qing Qu、Jiahui Huang、Chunkang Chang、Kunwei Shen、Xiaosong Chen、Min Lu

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Department of General Surgery,Comprehensive Breast Health Center,Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

Shanghai Institute of Hematology,State Key Laboratory of Medical Genomics,National Research Center for Translational Medicine(Shanghai),Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

Department of Hematology,Shanghai Institute of Hematology,Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

Department of Hematology,Shanghai Jiao Tong University Affiliated Sixth People's Hospital,Shanghai 200025,China

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国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金SJTU Transmed Awards ResearchShanghai Municipal Education Commission-Gaofeng Clinical MedicineShanghai Municipal Education Commission-Gaofeng Clinical MedicineShanghai Excellent Youth Academic LeaderProgram of Shanghai Science and Technology CommitteeDawn Program of Shanghai Education CommissionSamuel Waxman Cancer Research FoundationFoundation of National Facility for Translational Medicine(Shanghai)

821300758207329281772797820729378207289782002773819001578283182017200720XD142270021S1190010021SG18NRCTMSH-2021-08

2024

10.1007/s11684-023-1016-8

医学前沿
高等教育出版社

医学前沿

CSTPCD
影响因子：1.362
ISSN：2095-0217
年,卷(期)：2024.18(2)
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