MON-316 - Mechanistic Insights into the Role of Dimethyl Fumarate at Preventing Recurrence of ER-Positive Breast Cancer

Background
Endocrine therapies including tamoxifen or aromatase inhibitors significantly improve breast cancer patients’ short- and long-term outcomes. However, despite endocrine therapy’s proven therapeutic effect, 30%-50% percent of breast cancer patients will suffer recurrence and death eventually. A number of histo-clinical markers and gene-based recurrence scores can predict fairly well the risk of recurrence, but this has not translated into therapeutic options for patients at high risk of recurrence; other than chemotherapy, there is no other drug option available to high-risk patients. Dimethyl fumarate (DMF, Tecfidera) is an FDA-approved drug used for multiple sclerosis and psoriasis treatment. We have shown that DMF prevents recurrence of ER+ xenograft tumors after tamoxifen is withdrawn. Mechanistically, DMF reacts with cysteines to form a stable covalent adduct known as succination. Our goal is to use DMF as a chemical biology tool to identify druggable targets and pathways driving tumor recurrence. In turn, this mechanistic insight will help further establish DMF is a viable option against recurrence.
Results
To identify potential DMF targets in residual tumor cells in vivo, we conducted activity-based chemical proteomics to map proteins that are succinated by DMF in ER+ xenografts. We identified Interferon Regulatory Factor 9 (IRF9), a transcription factor that mediates type I interferon (IFN) response, as a succination target of DMF in residual tumor cells. We also conducted transcriptomics to profile tumor-wide changes upon DMF treatment. The top pathways downregulated by DMF+tamoxifen are IFN signaling. Under IFNα treatment of ER+ breast cancer cells, DMF inhibited multiple interferon-stimulated genes, such as ISG15, LGALS9, and IFIT3. The same effect was observed with siIRF9. IFN signaling was high in mammosphere and inhibition of IRF9, by siIRF9 or DMF, attenuated mammosphere formation. IRF9 succination by DMF disrupted the IRF9-STAT2 complex that mediates IFN signaling.

Conclusion:
We found that DMF inhibits the intrinsically elevated interferon (IFN) pathway in persister/residual tumor cells that fail endocrine therapy in vivo. DMF also inhibits IFN signaling that is required for stem-like properties. Mechanistically, DMF succinates IRF9, the transcription factor mediating IFN signaling, and disrupts its complex with STAT2. Recent evidence on tumor cell-intrinsic and microenvironment-derived IFN signaling in ER+ breast cancer has revitalized the topic and has suggested therapeutic opportunities by exploiting IFN signaling. We provide the first evidence that DMF can achieve IFN-IRF9 inhibition to prevent tumor recurrence.

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