Abstract P5-01-25: Romidepsin Targets HDAC1/2 to Induce Ferroptosis in TNBC Enhancing Chemosensitivity to Eribulin

Abstract Triple-negative breast cancer (TNBC) is a highly aggressive solid tumor with limited clinical treatment options, necessitating the urgent development of new drugs or therapeutic strategies. Romidepsin is a selective inhibitor of HDAC1/2 with notable antitumor activity in lymphomas, but its therapeutic efficacy in solid tumors like TNBC remains unclear. Our research reveals that romidepsin significantly induces ferroptosis in TNBC cells. Through RNA-seq analysis, we identified that romidepsin markedly alters the expression of several ferroptosis-related genes. Romidepsin regulates GSH metabolic reprogramming via the SLC7A11-CHAC1-GLS2 axis and causes iron overload in TNBC cells by modulating the Keap1-Nrf2-Hmox1 axis. Additionally, it promotes lipid peroxidation by upregulating the LPCAT3-POR-CYB5R1 axis. These biological functions of romidepsin are achieved through epigenetic modifications of target genes by HDAC1/2. Knockdown of HDAC1 or HDAC2 exacerbated romidepsin-induced ferroptosis in TNBC cells. To explore the clinical potential of romidepsin in TNBC treatment, we investigated its effects in combination with several first-line chemotherapeutic agents, including PTX and DDP, through cell viability assays. We found that romidepsin significantly enhanced the antitumor activity of multiple chemotherapy agents, with the most pronounced synergistic effect observed in combination with the anti-microtubule agent eribulin. The combination of romidepsin and eribulin effectively inhibited TNBC proliferation and promoted apoptosis and ferroptosis, demonstrating potent antitumor effects both in vitro and in vivo. Our study provides novel insights into the potential application of romidepsin in the clinical treatment of TNBC. The combination of romidepsin and eribulin holds promise for future clinical application in TNBC therapy. Citation Format: Weipeng Zhao, Xichuan Li, Xing Yang, Yulong Wang, Shuling Wang, Qian Liu. Romidepsin Targets HDAC1/2 to Induce Ferroptosis in TNBC Enhancing Chemosensitivity to Eribulin [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-01-25.