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

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.

Keywords

p53 mutation / triple-negative breast cancer / decitabine / DNMT1 / IRF7 / innate immune response

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Acknowledgements

We sincerely appreciate all of the participants of the DETECT trial for their coordination and devotion. We also would like to thank all the specialist nurses and secretaries for their diligent work in database maintenance and follow-up update.

These studies were supported by the National Natural Science Foundation of China (No. 82130075 to Min Lu, No. 82073292 to Min Lu, No. 81772797 to Xiaosong Chen, No. 82072937 to Xiaosong Chen, No. 82072897 to Kunwei Shen, No. 82002773 to Zheng Wang, No. 81900157 to Ying Liang), SJTU Trans-med Awards Research (to Min Lu), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine (No. 828318 to Min Lu and No. 20172007 to Xiaosong Chen), Shanghai Excellent Youth Academic Leader (No. 20XD1422700 to Min Lu), Program of Shanghai Science and Technology Committee (No. 21S11900100 to Min Lu), Dawn Program of Shanghai Education Commission (No. 21SG18 to Min Lu), Samuel Waxman Cancer Research Foundation (to Min Lu), and Foundation of National Facility for Translational Medicine (Shanghai) (No. NRCTM(SH)-2021-08).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-1016-8 and is accessible for authorized users.

Compliance with ethics guidelines

Conflicts of interest 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, and Min Lu have declared that they have no conflict of interest.

The study was approved by the Ruijin Hospital Ethics Committee and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for being included in the study.

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