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

IF 3.9 3区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Frontiers of Medicine Pub Date : 2023-12-29 DOI:10.1007/s11684-023-1016-8

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Abstract

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.

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地西他滨诱导 p53 突变的三阴性乳腺癌患者产生 IRF7 介导的免疫反应：一项临床和转化研究

摘要 p53 在半数癌症病例中发生突变。然而，目前还没有针对 p53 的药物获得批准。在此，我们将地西他滨重新定位为三阴性乳腺癌（TNBC）的靶向药物，TNBC是一种p53突变频繁、预后极差的亚型乳腺癌。在一项针对 132 例 TNBC 病例的组织芯片回顾性研究中，DNMT1 过表达与 p53 突变（P = 0.037）和总生存期（OS）差（P = 0.010）相关。在一项DEciTabinE和卡铂治疗TNBC（DETECT）的前瞻性试验（NCT03295552）中，地西他滨联合卡铂治疗12例IV期TNBC患者的客观反应率（ORR）为42%。在9名有TP53测序结果的试验患者中，6名p53突变患者的ORR（3/6 vs. 0/3）和OS（16.0 vs. 4.0个月）均高于p53野生型患者。在一项机理研究中，与具有野生型 p53 的细胞系相比，携带 DETECT 衍生 p53 突变的同源 TNBC 细胞系表现出更高的 DNMT1 表达和地西他滨敏感性。在 DETECT 试验中，地西他滨诱导了强烈的免疫反应，在 p53 突变的 TNBC 细胞系（上调了 16 倍）和反应最强烈的 TNBC 患者中，先天性免疫因子 IRF7 的上调非常明显。我们的综合研究揭示了将地西他滨重新用于治疗 p53 突变的 TNBC 的潜力，并建议将 IRF7 作为地西他滨治疗的潜在生物标志物。

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来源期刊

Frontiers of Medicine ONCOLOGYMEDICINE, RESEARCH & EXPERIMENTAL&-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

18.30

自引率

0.00%

发文量

800

期刊介绍： Frontiers of Medicine is an international general medical journal sponsored by the Ministry of Education of China. The journal is jointly published by the Higher Education Press and Springer. Since the first issue of 2010, this journal has been indexed in PubMed/MEDLINE. Frontiers of Medicine is dedicated to publishing original research and review articles on the latest advances in clinical and basic medicine with a focus on epidemiology, traditional Chinese medicine, translational research, healthcare, public health and health policies.