Abstract 5830: Combining DNA methylation inhibition and STING agonist in the treatment of metastatic triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is an aggressive breast cancer associated with early metastatic events leading to a poor prognosis. According to the American Cancer Society, the 5-year relative survival rate is 91% in patients with localized TNBC but only 12% for those with metastatic TNBC. Thus, there is an urgent need to understand the mechanisms that drive TNBC metastasis to uncover more effective therapeutic approaches. In this regard, we first profiled the RNA-Seq and DNA methylation enrichment in 8 metastatic TNBC cell lines with bone, liver and lung organotropism and then compared them to 3 parental TNBC cell lines. The RNA-Seq data showed that the downregulation of IFN-type-1 pathways is associated with TNBC metastatic organotropism in the lung, liver and bone. Surprisingly, the DNA methylation profiling revealed that the IFN-type-1-related genes are under DNA methylation regulation. The inhibition of DNA methylation with decitabine increased the expression of IFNβ gene in metastatic TNBC cell lines. This supports that targeting DNA methylation and stimulating the IFN-type-1 pathway could represent a new vulnerability for metastatic-TNBC. In this regard, the use of STING agonist, a known stimulator of IFN-type-1, synergizes with decitabine in reducing the viability of 6 metastatic TNBC cell lines with lung, liver and bone organotropism. More importantly, the decitabine/STING therapy showed a potent effect in targeting TNBC metastatic lesions in vivo and improved survival. Altogether, this work suggests that the DNA methylation inhibition and the stimulation of the IFN-type-1 pathway represent a new approach to target the metastatic-TNBC. Citation Format: Sofiane Berrazouane, Xiaoting You, Jack Su, Margarita Bartish, Rhea Dumitrescu, Marios Langke, Young Im, Benjamin Lebeau, Sonia del Rincon, Josie Ursini-Siegel, Michael Witcher. Combining DNA methylation inhibition and STING agonist in the treatment of metastatic triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5830.