Abstract 2728: Lysine acetyltransferase inhibitor MG149 reduces tumor recurrence in triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression. This lack of targetable receptors makes TNBC particularly challenging to treat. Identifying therapeutic targets which can be targeted to prevent TNBC recurrence is crucial for developing better treatments. By studying mechanisms driving recurrence we hypothesized that post-therapy changes in cancer cell epigenetics contribute to recurrence and that using epigenetic drugs to inhibit these changes could reduce the likelihood of relapse and improve patient outcomes. Thus, the aim of this study was to identify novel epigenetic regulators of tumor recurrence in TNBC. Using TNBC cell line MDA-MB-231, we generated a model of recurrence using Doxorubicin (Doxo). We performed a drug screen using commercially available epigenetic inhibitors in vitro and in vivo to identify novel epigenetic regulators of tumor recurrence. Cell count (in vitro) and tumor volumes (in vivo) were used to determine the anti-tumor effects. Weight loss was used as an index of toxicity in mice. Supporting our hypothesis, we observed notable differences in the levels of various epigenetic regulators before and after Doxo treatment and during recurrence. Additionally, we discovered that certain epigenetic drugs could prevent recurrence in culture, but only when administered sequentially following Doxo exposure, and not when used in prepriming or in combination. Sequential administration of the KAT inhibitor MG149 effectively controlled tumor growth in NSG mice with MDA-MB-231 and PDX1 tumors. MG149 was also found to enhance the effectiveness of other standard chemotherapy drugs, including paclitaxel and cyclophosphamide. In vitro and in vivo studies showed that sequential use of MG149 with Doxo increases DNA damage (gamma H2AX) and apoptosis (annexinV/7AAD) and significantly reduces the expression of cell cycle inhibitors p21, p27, and p53. These findings suggest a model where suppression of cell cycle inhibitors and persistent DNA damage post-therapy exposure with MG149 leads to increased apoptosis, reduced recurrence from therapy, and enhanced tumor growth control. Our findings indicate that new epigenetic states are formed following chemotherapy exposure, which can be therapeutically targeted to prevent recurrence in TNBC. Citation Format: Christiana O. Appiah, Manjulata Singh, Christiane Morecock, Aashka Shah, Abigail Andrews, Nasser Alabdulaly, Akash Jagdeesh, Sidney Umana-Guardado, Jonathan Yun, Laura Graham, Carson Walker, Madelyn Lorenz, Shengzhe Shang, Anthony Faber, Andrew Souers, Dipankar Bandyopadhyay, Steve Grant, Gordon Ginder, Jennifer Kobilinski, Harry D. Bear, Joshua C. Harrell, Joseph W. Landry. Lysine acetyltransferase inhibitor MG149 reduces tumor recurrence in 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 2728.