Abstract 5643: Aryl hydrocarbon receptor agonist ZSTK3744 overcomes chemotherapy resistance in TNBC

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis compared with other subtypes. Due to the lack of therapeutic targets, such as hormone receptors and human epidermal growth factor receptor 2, systemic chemotherapy remains the primary treatment option for TNBC. However, chemotherapy has limited benefits and some patients acquire resistance, further complicating treatment. New therapeutic approaches are urgently needed to overcome chemotherapy resistance in TNBC. ZSTK3744 is an aryl hydrocarbon receptor agonist developed as a novel therapeutic candidate for TNBC. ZSTK3744 has shown inhibitory effects on the proliferation of various cancer cell lines, including TNBC cell lines, in vitro. Moreover, it suppressed tumor growth in TNBC xenograft models. In this study, we evaluated the effects of ZSTK3744 on chemotherapy-resistant TNBC cells. Chemotherapy-resistant MDA-MB-468 cells, derived from TNBC, were developed through long-term exposure to adriamycin or paclitaxel. Compared to wild-type cells, the anti-tumor effects of adriamycin, paclitaxel, and eribulin were weakened in these resistant cells; however, ZSTK3744 maintained its efficacy. Transcriptome analysis was conducted to elucidate the mechanism of chemotherapy resistance, revealing alterations in several resistance-associated genes. In particular, upregulation of the ATP-binding cassette transporter 1 gene (ABCB1) was commonly observed in these cells. The anti-tumor effects of adriamycin, paclitaxel, and eribulin were reduced in cells with high ABCB1 expression, whereas those of ZSTK3744 were unaffected. Moreover, ZSTK3744 significantly inhibited tumor growth in xenograft models implanted with adriamycin-resistant MDA-MB-468 cells, showing a higher potency than eribulin. ZSTK3744 is a promising agent for overcoming chemotherapy-resistance in TNBC. Citation Format: Takahiro Ohashi, Kayoko Kawai-Asami, Sayuri Terada, Kotomi Akatsuka, Yuko Nagata, Shinsuke Hiramoto, Tsubasa Nagasaki, Eika Higashi, Ryuichiro Ohshita, Keiko Fukushima. Aryl hydrocarbon receptor agonist ZSTK3744 overcomes chemotherapy resistance in TNBC [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 5643.